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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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23 pages, 1111 KiB  
Review
Comparative Pathology of West Nile Virus in Humans and Non-Human Animals
by Alex D. Byas and Gregory D. Ebel
Pathogens 2020, 9(1), 48; https://doi.org/10.3390/pathogens9010048 - 07 Jan 2020
Cited by 39 | Viewed by 11843
Abstract
West Nile virus (WNV) continues to be a major cause of human arboviral neuroinvasive disease. Susceptible non-human vertebrates are particularly diverse, ranging from commonly affected birds and horses to less commonly affected species such as alligators. This review summarizes the pathology caused by [...] Read more.
West Nile virus (WNV) continues to be a major cause of human arboviral neuroinvasive disease. Susceptible non-human vertebrates are particularly diverse, ranging from commonly affected birds and horses to less commonly affected species such as alligators. This review summarizes the pathology caused by West Nile virus during natural infections of humans and non-human animals. While the most well-known findings in human infection involve the central nervous system, WNV can also cause significant lesions in the heart, kidneys and eyes. Time has also revealed chronic neurologic sequelae related to prior human WNV infection. Similarly, neurologic disease is a prominent manifestation of WNV infection in most non-human non-host animals. However, in some avian species, which serve as the vertebrate host for WNV maintenance in nature, severe systemic disease can occur, with neurologic, cardiac, intestinal and renal injury leading to death. The pathology seen in experimental animal models of West Nile virus infection and knowledge gains on viral pathogenesis derived from these animal models are also briefly discussed. A gap in the current literature exists regarding the relationship between the neurotropic nature of WNV in vertebrates, virus propagation and transmission in nature. This and other knowledge gaps, and future directions for research into WNV pathology, are addressed. Full article
(This article belongs to the Special Issue Pathogenesis of West Nile Virus)
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18 pages, 1507 KiB  
Review
Understanding Flavivirus Capsid Protein Functions: The Tip of the Iceberg
by Stephanea Sotcheff and Andrew Routh
Pathogens 2020, 9(1), 42; https://doi.org/10.3390/pathogens9010042 - 05 Jan 2020
Cited by 32 | Viewed by 7663
Abstract
Flaviviruses are enveloped positive-sense single-stranded RNA arboviruses, infectious to humans and many other animals and are transmitted primarily via tick or mosquito vectors. Capsid is the primary structural protein to interact with viral genome within virus particles and is therefore necessary for efficient [...] Read more.
Flaviviruses are enveloped positive-sense single-stranded RNA arboviruses, infectious to humans and many other animals and are transmitted primarily via tick or mosquito vectors. Capsid is the primary structural protein to interact with viral genome within virus particles and is therefore necessary for efficient packaging. However, in cells, capsid interacts with many proteins and nucleic acids and we are only beginning to understand the broad range of functions of flaviviral capsids. It is known that capsid dimers interact with the membrane of lipid droplets, aiding in both viral packaging and storage of capsid prior to packaging. However, capsid dimers can bind a range of nucleic acid templates in vitro, and likely interact with a range of targets during the flavivirus lifecycle. Capsid may interact with host RNAs, resulting in altered RNA splicing and RNA transcription. Capsid may also bind short interfering-RNAs and has been proposed to sequester these species to protect flaviviruses from the invertebrate siRNA pathways. Capsid can also be found in the nucleolus, where it wreaks havoc on ribosome biogenesis. Here we review flavivirus capsid structure, nucleic acid interactions and how these give rise to multiple functions. We also discuss how these features might be exploited either in the design of effective antivirals or novel vaccine strategies. Full article
(This article belongs to the Special Issue Vaccines against Alphaviruses and Flaviviruses)
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15 pages, 1301 KiB  
Article
Toxoplasma gondii Recombinant antigen AMA1: Diagnostic Utility of Protein Fragments for the Detection of IgG and IgM Antibodies
by Bartłomiej Ferra, Lucyna Holec-Gąsior, Justyna Gatkowska, Bożena Dziadek and Katarzyna Dzitko
Pathogens 2020, 9(1), 43; https://doi.org/10.3390/pathogens9010043 - 05 Jan 2020
Cited by 11 | Viewed by 3882
Abstract
Toxoplasma gondii is an important zoonotic protozoan that infects a wide variety of vertebrates as intermediate hosts. For this reason, the diagnosis of this disease is very important and requires continuous improvement. One possibility is to use recombinant antigens in serological tests. Apical [...] Read more.
Toxoplasma gondii is an important zoonotic protozoan that infects a wide variety of vertebrates as intermediate hosts. For this reason, the diagnosis of this disease is very important and requires continuous improvement. One possibility is to use recombinant antigens in serological tests. Apical membrane antigen 1 (AMA1), a protein located in specific secretory organelles (micronemes) of T. gondii, is very interesting in regard to its potential diagnostic utility. In the present study, we attempted to identify a fragment of the AMA1 protein with a high sensitivity and specificity for the serological diagnosis of human toxoplasmosis. The full-length AMA1 and two different fragments (AMA1N and AMA1C) were produced using an Escherichia coli expression system. After purification by metal affinity chromatography, recombinant proteins were tested for their utility as antigens in enzyme-linked immunosorbent assays (ELISAs) for the detection of IgG and IgM anti-T. gondii antibodies in human and mouse immune sera. Our data demonstrate that the full-length AMA1 recombinant antigen (corresponding to amino acid residues 67–569 of the native protein) has a better diagnostic potential than its N- or C-terminal fragments. This recombinant protein strongly interacts with specific anti-T. gondii IgG (99.4%) and IgM (80.0%) antibodies, and may be used for developing new tools for diagnostics of toxoplasmosis. Full article
(This article belongs to the Section Human Pathogens)
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17 pages, 1925 KiB  
Article
Analysis of Porcine Pro- and Anti-Inflammatory Cytokine Induction by S. suis In Vivo and In Vitro
by Florian S. Hohnstein, Marita Meurer, Nicole de Buhr, Maren von Köckritz-Blickwede, Christoph G. Baums, Gottfried Alber and Nicole Schütze
Pathogens 2020, 9(1), 40; https://doi.org/10.3390/pathogens9010040 - 03 Jan 2020
Cited by 14 | Viewed by 4348
Abstract
Weaning piglets are susceptible to the invasive Streptococcus (S.) suis infection, which can result in septicemia. The aim of this study was to investigate the cytokine profile induced upon S. suis infection of blood, to determine the cellular sources of those cytokines, and [...] Read more.
Weaning piglets are susceptible to the invasive Streptococcus (S.) suis infection, which can result in septicemia. The aim of this study was to investigate the cytokine profile induced upon S. suis infection of blood, to determine the cellular sources of those cytokines, and to study the potential effects of the induced cytokines on bacterial killing. We measured TNF-α, IL-6, IFN-γ, IL-17A and IL-10 after an experimental intravenous infection with S. suis serotype 2 in vivo, and analyzed whole blood, peripheral blood mononuclear cells (PBMC) and separated leukocytes to identify the cytokine-producing cell type(s). In addition, we used a reconstituted whole blood assay to investigate the effect of TNF-α on bacterial killing in the presence of different S. suis-specific IgG levels. An increase in IL-6 and IL-10, but not in IFN-γ or IL-17A, was observed in two of three piglets with pronounced bacteremia 16 to 20 h after infection, but not in piglets with controlled bacteremia. Our results confirmed previous findings that S. suis induces TNF-α and IL-6 and could demonstrate that TNF-α is produced by monocytes in vitro. We further found that IL-10 induction resulted in reduced secretion of TNF-α and IL-6. Rapid induction of TNF-α was, however, not crucial for in vitro bacterial killing, not even in the absence of specific IgG. Full article
(This article belongs to the Special Issue Update on Streptococcus suis Research and Prevention in the Era of Antibiotic Restriction - 4th International Workshop on Streptococcus suis)
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13 pages, 4214 KiB  
Article
Comparison of the Pathogenicity of Two Different Branches of Senecavirus a Strain in China
by Huawei Zhang, Pin Chen, Genxi Hao, Wenqiang Liu, Huanchun Chen, Ping Qian and Xiangmin Li
Pathogens 2020, 9(1), 39; https://doi.org/10.3390/pathogens9010039 - 02 Jan 2020
Cited by 14 | Viewed by 2616
Abstract
Senecavirus A (SVA), an emerging infectious disease, is associated with the porcine idiopathic vesicular disease. Here, the pathogenesis of different strains of SVA was investigated in growing-finishing pigs. We aimed to evaluate the replication characteristics, virus particle morphology, clinical signs, and vesicular lesions [...] Read more.
Senecavirus A (SVA), an emerging infectious disease, is associated with the porcine idiopathic vesicular disease. Here, the pathogenesis of different strains of SVA was investigated in growing-finishing pigs. We aimed to evaluate the replication characteristics, virus particle morphology, clinical signs, and vesicular lesions in comparison with two different strains of SVA. The animals were infected with SVA HB-CH-2016 or CH/AH-02/2017 by intranasal routes (3 mL, 109TCID50/mL) and monitored daily for 14 days post-inoculation (dpi) for clinical signs and vesicular lesions. Viremia or viral shedding was detected in the blood, fecal swab, and nasal swab samples. Results showed no distinct differences in plaque size, replication ability, and characteristic virions between SVA HB-CH-2016 and CH/AH-02/2017 strains. Animal experimental results showed that both SVA CH/AH-02/2017 and SVA HB-CH-2016 could infect pigs. However, an obvious difference in the pathogenicity and dynamics of infection was observed between SVA HB-CH-2016 and CH/AH-02/2017 strains. The pathogenesis of SVA CH/AH-02/2017 was similar to that of published results of USA strains, whereas the SVA HB-CH-2016 strain had low pathogenicity to pigs. Clinical signs and vesicular lesions were observed in SVA CH/AH-02/2017-infected pigs. Additionally, the different branches of SVA should be capable of inducing broad cross-reactive neutralizing antibodies, which play an important role in clearing the SVA virus. This study of animal models for SVA infection will be beneficial to develop vaccines and antivirals. Full article
(This article belongs to the Section Animal Pathogens)
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19 pages, 2112 KiB  
Article
The Cell-Cycle Regulatory Protein p21CIP1/WAF1 Is Required for Cytolethal Distending Toxin (Cdt)-Induced Apoptosis
by Bruce J. Shenker, Lisa M. Walker, Ali Zekavat, Robert H. Weiss and Kathleen Boesze-Battaglia
Pathogens 2020, 9(1), 38; https://doi.org/10.3390/pathogens9010038 - 02 Jan 2020
Cited by 10 | Viewed by 3024
Abstract
The Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) induces lymphocytes to undergo cell-cycle arrest and apoptosis; toxicity is dependent upon the active Cdt subunit, CdtB. We now demonstrate that p21CIP1/WAF1 is critical to Cdt-induced apoptosis. Cdt induces increases in the levels of p21 [...] Read more.
The Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) induces lymphocytes to undergo cell-cycle arrest and apoptosis; toxicity is dependent upon the active Cdt subunit, CdtB. We now demonstrate that p21CIP1/WAF1 is critical to Cdt-induced apoptosis. Cdt induces increases in the levels of p21CIP1/WAF1 in lymphoid cell lines, Jurkat and MyLa, and in primary human lymphocytes. These increases were dependent upon CdtB’s ability to function as a phosphatidylinositol (PI) 3,4,5-triphosphate (PIP3) phosphatase. It is noteworthy that Cdt-induced increases in the levels of p21CIP1/WAF1 were accompanied by a significant decline in the levels of phosphorylated p21CIP1/WAF1. The significance of Cdt-induced p21CIP1/WAF1 increase was assessed by preventing these changes with a two-pronged approach; pre-incubation with the novel p21CIP1/WAF1 inhibitor, UC2288, and development of a p21CIP1/WAF1-deficient cell line (Jurkatp21−) using clustered regularly interspaced short palindromic repeats (CRISPR)/cas9 gene editing. UC2288 blocked toxin-induced increases in p21CIP1/WAF1, and JurkatWT cells treated with this inhibitor exhibited reduced susceptibility to Cdt-induced apoptosis. Likewise, Jurkatp21− cells failed to undergo toxin-induced apoptosis. The linkage between Cdt, p21CIP1/WAF1, and apoptosis was further established by demonstrating that Cdt-induced increases in levels of the pro-apoptotic proteins Bid, Bax, and Bak were dependent upon p21CIP1/WAF1 as these changes were not observed in Jurkatp21− cells. Finally, we determined that the p21CIP1/WAF1 increases were dependent upon toxin-induced increases in the level and activity of the chaperone heat shock protein (HSP) 90. We propose that p21CIP1/WAF1 plays a key pro-apoptotic role in mediating Cdt-induced toxicity. Full article
(This article belongs to the Special Issue Aggregatibacter actinomycetemcomitans—Gram-Negative Bacterial Pathogen)
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23 pages, 4073 KiB  
Article
The Xylella fastidiosa-Resistant Olive Cultivar “Leccino” Has Stable Endophytic Microbiota during the Olive Quick Decline Syndrome (OQDS)
by Marzia Vergine, Joana B. Meyer, Massimiliano Cardinale, Erika Sabella, Martin Hartmann, Paolo Cherubini, Luigi De Bellis and Andrea Luvisi
Pathogens 2020, 9(1), 35; https://doi.org/10.3390/pathogens9010035 - 31 Dec 2019
Cited by 34 | Viewed by 6239
Abstract
Xylella fastidiosa is a highly virulent pathogen that causes Olive Quick Decline Syndrome (OQDS), which is currently devastating olive plantations in the Salento region (Apulia, Southern Italy). We explored the microbiome associated with X. fastidiosa-infected (Xf-infected) and -uninfected (Xf [...] Read more.
Xylella fastidiosa is a highly virulent pathogen that causes Olive Quick Decline Syndrome (OQDS), which is currently devastating olive plantations in the Salento region (Apulia, Southern Italy). We explored the microbiome associated with X. fastidiosa-infected (Xf-infected) and -uninfected (Xf-uninfected) olive trees in Salento, to assess the level of dysbiosis and to get first insights into the potential role of microbial endophytes in protecting the host from the disease. The resistant cultivar “Leccino” was compared to the susceptible cultivar “Cellina di Nardò”, in order to identify microbial taxa and parameters potentially involved in resistance mechanisms. Metabarcoding of 16S rRNA genes and fungal ITS2 was used to characterize both total and endophytic microbiota in olive branches and leaves. “Cellina di Nardò” showed a drastic dysbiosis after X. fastidiosa infection, while “Leccino” (both infected and uninfected) maintained a similar microbiota. The genus Pseudomonas dominated all “Leccino” and Xf-uninfected “Cellina di Nardò” trees, whereas Ammoniphilus prevailed in Xf-infected “Cellina di Nardò”. Diversity of microbiota in Xf-uninfected “Leccino” was higher than in Xf-uninfected “Cellina di Nardò”. Several bacterial taxa specifically associated with “Leccino” showed potential interactions with X. fastidiosa. The maintenance of a healthy microbiota with higher diversity and the presence of cultivar-specific microbes might support the resistance of “Leccino” to X. fastidiosa. Such beneficial bacteria might be isolated in the future for biological treatment of the OQDS. Full article
(This article belongs to the Section Plant Pathogens)
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19 pages, 2039 KiB  
Article
Membrane Binding, Cellular Cholesterol Content and Resealing Capacity Contribute to Epithelial Cell Damage Induced by Suilysin of Streptococcus suis
by Désirée Vötsch, Maren Willenborg, Walter M.R. Oelemann, Graham Brogden and Peter Valentin-Weigand
Pathogens 2020, 9(1), 33; https://doi.org/10.3390/pathogens9010033 - 30 Dec 2019
Cited by 7 | Viewed by 2732
Abstract
Streptococcus (S.) suis is a major cause of economic losses in the pig industry worldwide and is an emerging zoonotic pathogen. One important virulence-associated factor is suilysin (SLY), a toxin that belongs to the family of cholesterol-dependent pore-forming cytolysins (CDC). However, [...] Read more.
Streptococcus (S.) suis is a major cause of economic losses in the pig industry worldwide and is an emerging zoonotic pathogen. One important virulence-associated factor is suilysin (SLY), a toxin that belongs to the family of cholesterol-dependent pore-forming cytolysins (CDC). However, the precise role of SLY in host–pathogen interactions is still unclear. Here, we investigated the susceptibility of different respiratory epithelial cells to SLY, including immortalized cell lines (HEp-2 and NPTr cells), which are frequently used in in vitro studies on S. suis virulence mechanisms, as well as primary porcine respiratory cells, which represent the first line of barrier during S. suis infections. SLY-induced cell damage was determined by measuring the release of lactate dehydrogenase after infection with a virulent S. suis serotype 2 strain, its isogenic SLY-deficient mutant strain, or treatment with the recombinant protein. HEp-2 cells were most susceptible, whereas primary epithelial cells were hardly affected by the toxin. This prompted us to study possible explanations for these differences. We first investigated the binding capacity of SLY using flow cytometry analysis. Since binding and pore-formation of CDC is dependent on the membrane composition, we also determined the cellular cholesterol content of the different cell types using TLC and HPLC. Finally, we examined the ability of those cells to reseal SLY-induced pores using flow cytometry analysis. Our results indicated that the amount of membrane-bound SLY, the cholesterol content of the cells, as well as their resealing capacity all affect the susceptibility of the different cells regarding the effects of SLY. These findings underline the differences of in vitro pathogenicity models and may further help to dissect the biological role of SLY during S. suis infections. Full article
(This article belongs to the Special Issue Update on Streptococcus suis Research and Prevention in the Era of Antibiotic Restriction - 4th International Workshop on Streptococcus suis)
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22 pages, 1290 KiB  
Review
The Notorious Soilborne Pathogenic Fungus Sclerotinia sclerotiorum: An Update on Genes Studied with Mutant Analysis
by Shitou Xia, Yan Xu, Ryan Hoy, Julia Zhang, Lei Qin and Xin Li
Pathogens 2020, 9(1), 27; https://doi.org/10.3390/pathogens9010027 - 27 Dec 2019
Cited by 40 | Viewed by 9533
Abstract
Ascomycete Sclerotinia sclerotiorum (Lib.) de Bary is one of the most damaging soilborne fungal pathogens affecting hundreds of plant hosts, including many economically important crops. Its genomic sequence has been available for less than a decade, and it was recently updated with higher [...] Read more.
Ascomycete Sclerotinia sclerotiorum (Lib.) de Bary is one of the most damaging soilborne fungal pathogens affecting hundreds of plant hosts, including many economically important crops. Its genomic sequence has been available for less than a decade, and it was recently updated with higher completion and better gene annotation. Here, we review key molecular findings on the unique biology and pathogenesis process of S. sclerotiorum, focusing on genes that have been studied in depth using mutant analysis. Analyses of these genes have revealed critical players in the basic biological processes of this unique pathogen, including mycelial growth, appressorium establishment, sclerotial formation, apothecial and ascospore development, and virulence. Additionally, the synthesis has uncovered gaps in the current knowledge regarding this fungus. We hope that this review will serve to build a better current understanding of the biology of this under-studied notorious soilborne pathogenic fungus. Full article
(This article belongs to the Section Plant Pathogens)
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14 pages, 5535 KiB  
Article
Genome-Wide Analysis of Cyclophilin Proteins in 21 Oomycetes
by Yan Zhang, Kyle Fletcher, Rongkui Han, Richard Michelmore and Ruiwu Yang
Pathogens 2020, 9(1), 24; https://doi.org/10.3390/pathogens9010024 - 26 Dec 2019
Cited by 3 | Viewed by 2995
Abstract
Cyclophilins (CYPs), a highly-conserved family of proteins, belong to a subgroup of immunophilins. Ubiquitous in eukaryotes and prokaryotes, CYPs have peptidyl-prolyl cis–trans isomerase (PPIase) activity and have been implicated as virulence factors in plant pathogenesis by oomycetes. We identified 16 CYP orthogroups from [...] Read more.
Cyclophilins (CYPs), a highly-conserved family of proteins, belong to a subgroup of immunophilins. Ubiquitous in eukaryotes and prokaryotes, CYPs have peptidyl-prolyl cis–trans isomerase (PPIase) activity and have been implicated as virulence factors in plant pathogenesis by oomycetes. We identified 16 CYP orthogroups from 21 diverse oomycetes. Each species was found to encode 15 to 35 CYP genes. Three of these orthogroups contained proteins with signal peptides at the N-terminal end, suggesting a role in secretion. Multidomain analysis revealed five conserved motifs of the CYP domain of oomycetes shared with other eukaryotic PPIases. Expression analysis of CYP proteins in different asexual life stages of the hemibiotrophic Phytophthora infestans and the biotrophic Plasmopara halstedii demonstrated distinct expression profiles between life stages. In addition to providing detailed comparative information on the CYPs in multiple oomycetes, this study identified candidate CYP effectors that could be the foundation for future studies of virulence. Full article
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23 pages, 5544 KiB  
Article
Chromosomal Conjugative and Mobilizable Elements in Streptococcus suis: Major Actors in the Spreading of Antimicrobial Resistance and Bacteriocin Synthesis Genes
by Virginie Libante, Yves Nombre, Charles Coluzzi, Johan Staub, Gérard Guédon, Marcelo Gottschalk, Sarah Teatero, Nahuel Fittipaldi, Nathalie Leblond-Bourget and Sophie Payot
Pathogens 2020, 9(1), 22; https://doi.org/10.3390/pathogens9010022 - 25 Dec 2019
Cited by 26 | Viewed by 4572
Abstract
Streptococcus suis is a zoonotic pathogen suspected to be a reservoir of antimicrobial resistance (AMR) genes. The genomes of 214 strains of 27 serotypes were screened for AMR genes and chromosomal Mobile Genetic Elements (MGEs), in particular Integrative Conjugative Elements (ICEs) and Integrative [...] Read more.
Streptococcus suis is a zoonotic pathogen suspected to be a reservoir of antimicrobial resistance (AMR) genes. The genomes of 214 strains of 27 serotypes were screened for AMR genes and chromosomal Mobile Genetic Elements (MGEs), in particular Integrative Conjugative Elements (ICEs) and Integrative Mobilizable Elements (IMEs). The functionality of two ICEs that host IMEs carrying AMR genes was investigated by excision tests and conjugation experiments. In silico search revealed 416 ICE-related and 457 IME-related elements. These MGEs exhibit an impressive diversity and plasticity with tandem accretions, integration of ICEs or IMEs inside ICEs and recombination between the elements. All of the detected 393 AMR genes are carried by MGEs. As previously described, ICEs are major vehicles of AMR genes in S. suis. Tn5252-related ICEs also appear to carry bacteriocin clusters. Furthermore, whereas the association of IME-AMR genes has never been described in S. suis, we found that most AMR genes are actually carried by IMEs. The autonomous transfer of an ICE to another bacterial species (Streptococcus thermophilus)—leading to the cis-mobilization of an IME carrying tet(O)—was obtained. These results show that besides ICEs, IMEs likely play a major role in the dissemination of AMR genes in S. suis. Full article
(This article belongs to the Special Issue Update on Streptococcus suis Research and Prevention in the Era of Antibiotic Restriction - 4th International Workshop on Streptococcus suis)
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11 pages, 1358 KiB  
Communication
Human Microglia Respond to Malaria-Induced Extracellular Vesicles
by Smart Ikechukwu Mbagwu, Nils Lannes, Michael Walch, Luis Filgueira and Pierre-Yves Mantel
Pathogens 2020, 9(1), 21; https://doi.org/10.3390/pathogens9010021 - 24 Dec 2019
Cited by 20 | Viewed by 3995
Abstract
Microglia are the chief immune cells of the brain and have been reported to be activated in severe malaria. Their activation may drive towards neuroinflammation in cerebral malaria. Malaria-infected red blood cell derived-extracellular vesicles (MiREVs) are produced during the blood stage of malaria [...] Read more.
Microglia are the chief immune cells of the brain and have been reported to be activated in severe malaria. Their activation may drive towards neuroinflammation in cerebral malaria. Malaria-infected red blood cell derived-extracellular vesicles (MiREVs) are produced during the blood stage of malaria infection. They mediate intercellular communication and immune regulation, among other functions. During cerebral malaria, the breakdown of the blood–brain barrier can promote the migration of substances such as MiREVs from the periphery into the brain, targeting cells such as microglia. Microglia and extracellular vesicle interactions in different pathological conditions have been reported to induce neuroinflammation. Unlike in astrocytes, microglia–extracellular vesicle interaction has not yet been described in malaria infection. Therefore, in this study, we aimed to investigate the uptake of MiREVs by human microglia cells and their cytokine response. Human blood monocyte-derived microglia (MoMi) were generated from buffy coats of anonymous healthy donors using Ficoll-Paque density gradient centrifugation. The MiREVs were isolated from the Plasmodium falciparum cultures. They were purified by ultracentrifugation and labeled with PKH67 green fluorescent dye. The internalization of MiREVs by MoMi was observed after 4 h of co-incubation on coverslips placed in a 24-well plate at 37 °C using confocal microscopy. Cytokine-gene expression was investigated using rt-qPCR, following the stimulation of the MoMi cells with supernatants from the parasite cultures at 2, 4, and 24 h, respectively. MiREVs were internalized by the microglia and accumulated in the perinuclear region. MiREVs-treated cells increased gene expression of the inflammatory cytokine TNFα and reduced gene expression of the immune suppressive IL-10. Overall, the results indicate that MiREVs may act on microglia, which would contribute to enhanced inflammation in cerebral malaria. Full article
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16 pages, 969 KiB  
Review
Chloroplasts and Plant Immunity: Where Are the Fungal Effectors?
by Matthias Kretschmer, Djihane Damoo, Armin Djamei and James Kronstad
Pathogens 2020, 9(1), 19; https://doi.org/10.3390/pathogens9010019 - 24 Dec 2019
Cited by 65 | Viewed by 10669
Abstract
Chloroplasts play a central role in plant immunity through the synthesis of secondary metabolites and defense compounds, as well as phytohormones, such as jasmonic acid and salicylic acid. Additionally, chloroplast metabolism results in the production of reactive oxygen species and nitric oxide as [...] Read more.
Chloroplasts play a central role in plant immunity through the synthesis of secondary metabolites and defense compounds, as well as phytohormones, such as jasmonic acid and salicylic acid. Additionally, chloroplast metabolism results in the production of reactive oxygen species and nitric oxide as defense molecules. The impact of viral and bacterial infections on plastids and chloroplasts has been well documented. In particular, bacterial pathogens are known to introduce effectors specifically into chloroplasts, and many viral proteins interact with chloroplast proteins to influence viral replication and movement, and plant defense. By contrast, clear examples are just now emerging for chloroplast-targeted effectors from fungal and oomycete pathogens. In this review, we first present a brief overview of chloroplast contributions to plant defense and then discuss examples of connections between fungal interactions with plants and chloroplast function. We then briefly consider well-characterized bacterial effectors that target chloroplasts as a prelude to discussing the evidence for fungal effectors that impact chloroplast activities. Full article
(This article belongs to the Special Issue Pathogenesis of Fungal and Bacterial Microbes)
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11 pages, 627 KiB  
Review
Cancer-Associated Fibroblasts in Undifferentiated Nasopharyngeal Carcinoma: A Putative Role for the EBV-Encoded Oncoprotein, LMP1
by Mhairi A. Morris
Pathogens 2020, 9(1), 8; https://doi.org/10.3390/pathogens9010008 - 20 Dec 2019
Cited by 9 | Viewed by 4052
Abstract
Undifferentiated nasopharyngeal carcinoma (NPC) is 100% associated with Epstein–Barr virus (EBV) infection, and biopsies display variable levels of expression of the viral oncoprotein, latent membrane protein 1 (LMP1). Emerging evidence suggests an important role for cancer-associated fibroblasts (CAFs) in the NPC tumour microenvironment, [...] Read more.
Undifferentiated nasopharyngeal carcinoma (NPC) is 100% associated with Epstein–Barr virus (EBV) infection, and biopsies display variable levels of expression of the viral oncoprotein, latent membrane protein 1 (LMP1). Emerging evidence suggests an important role for cancer-associated fibroblasts (CAFs) in the NPC tumour microenvironment, yet the interaction between the virus, its latent gene products and the recruitment and activation of CAFs in the NPC tumour stroma remains unclear. This short review will discuss the current evidence for the importance of CAFs in NPC pathogenesis and outline a putative role for the EBV-encoded oncoprotein, LMP1, in governing tumour–stromal interactions. Full article
(This article belongs to the Section Human Pathogens)
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27 pages, 760 KiB  
Review
Atypical, Yet Not Infrequent, Infections with Neisseria Species
by Maria Victoria Humbert and Myron Christodoulides
Pathogens 2020, 9(1), 10; https://doi.org/10.3390/pathogens9010010 - 20 Dec 2019
Cited by 43 | Viewed by 11260
Abstract
Neisseria species are extremely well-adapted to their mammalian hosts and they display unique phenotypes that account for their ability to thrive within niche-specific conditions. The closely related species N. gonorrhoeae and N. meningitidis are the only two species of the genus recognized as [...] Read more.
Neisseria species are extremely well-adapted to their mammalian hosts and they display unique phenotypes that account for their ability to thrive within niche-specific conditions. The closely related species N. gonorrhoeae and N. meningitidis are the only two species of the genus recognized as strict human pathogens, causing the sexually transmitted disease gonorrhea and meningitis and sepsis, respectively. Gonococci colonize the mucosal epithelium of the male urethra and female endo/ectocervix, whereas meningococci colonize the mucosal epithelium of the human nasopharynx. The pathophysiological host responses to gonococcal and meningococcal infection are distinct. However, medical evidence dating back to the early 1900s demonstrates that these two species can cross-colonize anatomical niches, with patients often presenting with clinically-indistinguishable infections. The remaining Neisseria species are not commonly associated with disease and are considered as commensals within the normal microbiota of the human and animal nasopharynx. Nonetheless, clinical case reports suggest that they can behave as opportunistic pathogens. In this review, we describe the diversity of the genus Neisseria in the clinical context and raise the attention of microbiologists and clinicians for more cautious approaches in the diagnosis and treatment of the many pathologies these species may cause. Full article
(This article belongs to the Special Issue Neisseria gonorrhoeae Infections)
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22 pages, 1888 KiB  
Review
The Role of Pseudomonas aeruginosa Lipopolysaccharide in Bacterial Pathogenesis and Physiology
by Steven M. Huszczynski, Joseph S. Lam and Cezar M. Khursigara
Pathogens 2020, 9(1), 6; https://doi.org/10.3390/pathogens9010006 - 19 Dec 2019
Cited by 102 | Viewed by 13772
Abstract
The major constituent of the outer membrane of Gram-negative bacteria is lipopolysaccharide (LPS), which is comprised of lipid A, core oligosaccharide, and O antigen, which is a long polysaccharide chain extending into the extracellular environment. Due to the localization of LPS, it is [...] Read more.
The major constituent of the outer membrane of Gram-negative bacteria is lipopolysaccharide (LPS), which is comprised of lipid A, core oligosaccharide, and O antigen, which is a long polysaccharide chain extending into the extracellular environment. Due to the localization of LPS, it is a key molecule on the bacterial cell wall that is recognized by the host to deploy an immune defence in order to neutralize invading pathogens. However, LPS also promotes bacterial survival in a host environment by protecting the bacteria from these threats. This review explores the relationship between the different LPS glycoforms of the opportunistic pathogen Pseudomonas aeruginosa and the ability of this organism to cause persistent infections, especially in the genetic disease cystic fibrosis. We also discuss the role of LPS in facilitating biofilm formation, antibiotic resistance, and how LPS may be targeted by new antimicrobial therapies. Full article
(This article belongs to the Special Issue Pathogenesis of Fungal and Bacterial Microbes)
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15 pages, 2360 KiB  
Article
Genetic Changes in Experimental Populations of a Hybrid in the Cryptococcus neoformans Species Complex
by Kelly Dong, Man You and Jianping Xu
Pathogens 2020, 9(1), 3; https://doi.org/10.3390/pathogens9010003 - 18 Dec 2019
Cited by 13 | Viewed by 2255
Abstract
Hybrids between Cryptococcus neoformans and Cryptococcus deneoformans are commonly found in patients and the environment. However, the genetic stability of these hybrids remains largely unknown. Here, we established mutation accumulation lines of a diploid C. neoformans × C. deneoformans laboratory hybrid and analyzed [...] Read more.
Hybrids between Cryptococcus neoformans and Cryptococcus deneoformans are commonly found in patients and the environment. However, the genetic stability of these hybrids remains largely unknown. Here, we established mutation accumulation lines of a diploid C. neoformans × C. deneoformans laboratory hybrid and analyzed the genotypes at 33 markers distributed across all 14 chromosomes. Our analyses found that under standard culture conditions, heterozygosity at most loci was maintained over 800 mitotic generations, with an estimated 6.44 × 10−5 loss-of-heterozygosity (LoH) event per mitotic division. However, under fluconazole stress, the observed LoH frequency increased by > 50 folds for the two markers on Chromosome 1, all due to the loss of the fluconazole susceptible allele on this chromosome. Flow cytometry analyses showed that after the 40th transfer (120 days), 19 of the 20 lines maintained the original ploidy level (2N), while one line was between 2N and 3N. The combined flow cytometry, genotyping at 33 markers, and quantitative PCR analyses showed the allelic loss was compensated for by amplification of the resistant ERG11 allele in eight of the ten fluconazole-stress lines. Our results suggest that hybrids in C. neoformans species complex are generally stable but that they can undergo rapid adaptation to environmental stresses through LoH and gene duplication. Full article
(This article belongs to the Special Issue Pathogenesis of Fungal and Bacterial Microbes)
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59 pages, 2178 KiB  
Review
Lyme Disease Frontiers: Reconciling Borrelia Biology and Clinical Conundrums
by Vladimir V. Bamm, Jordan T. Ko, Iain L. Mainprize, Victoria P. Sanderson and Melanie K. B. Wills
Pathogens 2019, 8(4), 299; https://doi.org/10.3390/pathogens8040299 - 16 Dec 2019
Cited by 27 | Viewed by 16653
Abstract
Lyme disease is a complex tick-borne zoonosis that poses an escalating public health threat in several parts of the world, despite sophisticated healthcare infrastructure and decades of effort to address the problem. Concepts like the true burden of the illness, from incidence rates [...] Read more.
Lyme disease is a complex tick-borne zoonosis that poses an escalating public health threat in several parts of the world, despite sophisticated healthcare infrastructure and decades of effort to address the problem. Concepts like the true burden of the illness, from incidence rates to longstanding consequences of infection, and optimal case management, also remain shrouded in controversy. At the heart of this multidisciplinary issue are the causative spirochetal pathogens belonging to the Borrelia Lyme complex. Their unusual physiology and versatile lifestyle have challenged microbiologists, and may also hold the key to unlocking mysteries of the disease. The goal of this review is therefore to integrate established and emerging concepts of Borrelia biology and pathogenesis, and position them in the broader context of biomedical research and clinical practice. We begin by considering the conventions around diagnosing and characterizing Lyme disease that have served as a conceptual framework for the discipline. We then explore virulence from the perspective of both host (genetic and environmental predispositions) and pathogen (serotypes, dissemination, and immune modulation), as well as considering antimicrobial strategies (lab methodology, resistance, persistence, and clinical application), and borrelial adaptations of hypothesized medical significance (phenotypic plasticity or pleomorphy). Full article
(This article belongs to the Special Issue Pathogenesis of Fungal and Bacterial Microbes)
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13 pages, 4673 KiB  
Article
Endocytic Pathway of Feline Coronavirus for Cell Entry: Differences in Serotype-Dependent Viral Entry Pathway
by Tomomi Takano, Yumeho Wakayama and Tomoyoshi Doki
Pathogens 2019, 8(4), 300; https://doi.org/10.3390/pathogens8040300 - 16 Dec 2019
Cited by 14 | Viewed by 7227
Abstract
Feline coronavirus (FCoV) is a pathogen causing a lethal infectious disease in cats, feline infectious peritonitis. It has two serotypes (type I FCoV and type II FCoV). According to our previous study, type I FCoV infection is inhibited by compounds inducing intracellular cholesterol [...] Read more.
Feline coronavirus (FCoV) is a pathogen causing a lethal infectious disease in cats, feline infectious peritonitis. It has two serotypes (type I FCoV and type II FCoV). According to our previous study, type I FCoV infection is inhibited by compounds inducing intracellular cholesterol accumulation, whereas type II FCoV infection is not inhibited. Intracellular cholesterol accumulation was reported to disrupt late endosome function. Based on these findings, types I and II FCoV are considered to enter the cytosol through late and early endosomes, respectively. We investigated whether the antiviral activities of a late endosome trafficking inhibitor and cholesterol-accumulating agents are different between the FCoV serotypes. The late endosome trafficking inhibitor did not inhibit type II FCoV infection, but it inhibited type I FCoV infection. Type I FCoV infection was inhibited by cholesterol-accumulating triazoles, but not by non-cholesterol-accumulating triazoles. These phenomena were observed in both feline cell lines and feline primary macrophages. This study provides additional information on the differences in intracellular reproductive cycle between type I and type II FCoV. Full article
(This article belongs to the Special Issue Feline Infectious Peritonitis)
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13 pages, 1596 KiB  
Article
Genetic Basis and Physiological Effects of Lipid A Hydroxylation in Pseudomonas aeruginosa PAO1
by Alessandra Lo Sciuto, Matteo Cervoni, Roberta Stefanelli, Maria Concetta Spinnato, Alessandra Di Giamberardino, Carmine Mancone and Francesco Imperi
Pathogens 2019, 8(4), 291; https://doi.org/10.3390/pathogens8040291 - 10 Dec 2019
Cited by 16 | Viewed by 3513
Abstract
Modifications of the lipid A moiety of lipopolysaccharide influence the physicochemical properties of the outer membrane of Gram-negative bacteria. Some bacteria produce lipid A with a single hydroxylated secondary acyl chain. This hydroxylation is catalyzed by the dioxygenase LpxO, and is important for [...] Read more.
Modifications of the lipid A moiety of lipopolysaccharide influence the physicochemical properties of the outer membrane of Gram-negative bacteria. Some bacteria produce lipid A with a single hydroxylated secondary acyl chain. This hydroxylation is catalyzed by the dioxygenase LpxO, and is important for resistance to cationic antimicrobial peptides (e.g., polymyxins), survival in human blood, and pathogenicity in animal models. The lipid A of the human pathogen Pseudomonas aeruginosa can be hydroxylated in both secondary acyl chains, but the genetic basis and physiological role of these hydroxylations are still unknown. Through the generation of single and double deletion mutants in the lpxO1 and lpxO2 homologs of P. aeruginosa PAO1 and lipid A analysis by mass spectrometry, we demonstrate that both LpxO1 and LpxO2 are responsible for lipid A hydroxylation, likely acting on different secondary acyl chains. Lipid A hydroxylation does not appear to affect in vitro growth, cell wall stability, and resistance to human blood or antibiotics in P. aeruginosa. In contrast, it is required for infectivity in the Galleria mellonella infection model, without relevantly affecting in vivo persistence. Overall, these findings suggest a role for lipid A hydroxylation in P. aeruginosa virulence that could not be directly related to outer membrane integrity. Full article
(This article belongs to the Section Human Pathogens)
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18 pages, 3669 KiB  
Article
Phenotypic Characterization of Rhodococcus equi Biofilm Grown In Vitro and Inhibiting and Dissolving Activity of Azithromycin/Rifampicin Treatment
by Elisa Rampacci, Maria Luisa Marenzoni, Stefano Giovagnoli, Fabrizio Passamonti, Mauro Coletti and Donatella Pietrella
Pathogens 2019, 8(4), 284; https://doi.org/10.3390/pathogens8040284 - 04 Dec 2019
Cited by 6 | Viewed by 3192
Abstract
Microbial biofilm has been implicated in a wide range of chronic infections. In spite of the fact that Rhodococcus equi is a recognized cause of chronic disease in animals and humans, few studies have focused on the sessile phenotype of R. equi. [...] Read more.
Microbial biofilm has been implicated in a wide range of chronic infections. In spite of the fact that Rhodococcus equi is a recognized cause of chronic disease in animals and humans, few studies have focused on the sessile phenotype of R. equi. The aim of this research was to phenotypically characterize the biofilm development of R. equi and its answerability for hypo-responsiveness to macrolides and rifampicin. Biofilm formation is initiated by bacterial adhesion to the surface. In this work, the ability of R. equi to adhere to the surface of human lung epithelial cells was detected by a fluorometric adhesion test performed on 40 clinical isolates. Subsequently, the capability of R. equi to produce biofilm was investigated by colorimetric, fluorescence and scanning electron microscopy analysis, revealing a general slow growth of rhodococcal biofilm and different sessile phenotypes among field isolates, some also including filamented bacteria. Azithromycin treatment produced a higher long-term inhibition and dissolution of R. equi biofilms than rifampicin, while the two antibiotics combined boosted the anti-biofilm effect in a statistically significant manner, although this was not equally effective for all R. equi isolates. Increasing the MIC concentrations of drugs tenfold alone and in combination did not completely eradicate pre-formed R. equi biofilms, while a rifampicin-resistant isolate produced an exceptionally abundant extracellular matrix. These results have strengthened the hypothesis that biofilm production may occur as an antibiotic tolerance system in R. equi, potentially determining persistence and, eventually, chronic infection. Full article
(This article belongs to the Section Animal Pathogens)
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13 pages, 1679 KiB  
Article
Transcriptomic Analysis of Aggregatibacter actinomycetemcomitans Core and Accessory Genes in Different Growth Conditions
by Natalia O. Tjokro, Weerayuth Kittichotirat, Annamari Torittu, Riikka Ihalin, Roger E. Bumgarner and Casey Chen
Pathogens 2019, 8(4), 282; https://doi.org/10.3390/pathogens8040282 - 03 Dec 2019
Cited by 4 | Viewed by 2707
Abstract
Aggregatibacter actinomycetemcomitans genome can be divided into an accessory gene pool (found in some but not all strains) and a core gene pool (found in all strains). The functions of the accessory genes (genomic islands and non-island accessory genes) are largely unknown. We [...] Read more.
Aggregatibacter actinomycetemcomitans genome can be divided into an accessory gene pool (found in some but not all strains) and a core gene pool (found in all strains). The functions of the accessory genes (genomic islands and non-island accessory genes) are largely unknown. We hypothesize that accessory genes confer critical functions for A. actinomycetemcomitans in vivo. This study examined the expression patterns of accessory and core genes of A. actinomycetemcomitans in distinct growth conditions. We found similar expression patterns of island and non-island accessory genes, which were generally lower than the core genes in all growth conditions. The median expression levels of genomic islands were 29%–37% of the core genes in enriched medium but elevated to as high as 63% of the core genes in nutrient-limited media. Several putative virulence genes, including the cytolethal distending toxin operon, were found to be activated in nutrient-limited conditions. In conclusion, genomic islands and non-island accessory genes exhibited distinct patterns of expression from the core genes and may play a role in the survival of A. actinomycetemcomitans in nutrient-limited environments. Full article
(This article belongs to the Special Issue Aggregatibacter actinomycetemcomitans—Gram-Negative Bacterial Pathogen)
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9 pages, 267 KiB  
Article
The Prevalence of HSV, HHV-6, HPV and Mycoplasma genitalium in Chlamydia trachomatis positive and Chlamydia trachomatis Negative Urogenital Samples among Young Women in Finland
by Suvi Korhonen, Kati Hokynar, Tiina Eriksson, Kari Natunen, Jorma Paavonen, Matti Lehtinen and Mirja Puolakkainen
Pathogens 2019, 8(4), 276; https://doi.org/10.3390/pathogens8040276 - 01 Dec 2019
Cited by 5 | Viewed by 3579
Abstract
Chlamydia trachomatis, Mycoplasma genitalium, herpes simplex virus (HSV) and human papillomavirus (HPV) cause sexually transmitted infections. In addition, human herpesvirus 6 (HHV-6) may be a genital co-pathogen. The prevalence rates of HSV, HHV-6, HPV, M. genitalium, and the C. trachomatis [...] Read more.
Chlamydia trachomatis, Mycoplasma genitalium, herpes simplex virus (HSV) and human papillomavirus (HPV) cause sexually transmitted infections. In addition, human herpesvirus 6 (HHV-6) may be a genital co-pathogen. The prevalence rates of HSV, HHV-6, HPV, M. genitalium, and the C. trachomatis ompA genotypes were investigated by PCR in urogenital samples of the C. trachomatis nucleic acid amplification test positive (n = 157) and age-, community- and time-matched negative (n = 157) women. The prevalence of HPV DNA was significantly higher among the C. trachomatis positives than the C. trachomatis negatives (66% vs. 25%, p < 0.001). The prevalence of HSV (1.9% vs. 0%), HHV-6 (11% vs. 14%), and M. genitalium DNA (4.5% vs. 1.9%) was not significantly different between the C. trachomatis-positive and -negative women. Thirteen per cent of test-of-cure specimens tested positive for C. trachomatis. The prevalence of HSV, HHV-6, HPV, M. genitalium, and the C. trachomatis ompA genotypes did not significantly differ between those who cleared the C. trachomatis infection (n = 105) and those who did not (n = 16). The higher prevalence of HPV DNA among the C. trachomatis positives suggests greater sexual activity and increased risk for sexually transmitted pathogens. Full article
(This article belongs to the Special Issue Chlamydia trachomatis Infections)
12 pages, 6108 KiB  
Article
Immunosuppressive Compounds Affect the Fungal Growth and Viability of Defined Aspergillus Species
by Stanislaw Schmidt, Michael Hogardt, Asuman Demir, Frauke Röger and Thomas Lehrnbecher
Pathogens 2019, 8(4), 273; https://doi.org/10.3390/pathogens8040273 - 29 Nov 2019
Cited by 5 | Viewed by 2788
Abstract
Immunosuppressive drugs are administered to a number of patients; e.g., to allogeneic hematopoietic stem cell transplant recipients. Immunosuppressive drugs impair the immune system and thus increase the risk of invasive fungal disease, but may exhibit antifungal activity at the same time. We investigated [...] Read more.
Immunosuppressive drugs are administered to a number of patients; e.g., to allogeneic hematopoietic stem cell transplant recipients. Immunosuppressive drugs impair the immune system and thus increase the risk of invasive fungal disease, but may exhibit antifungal activity at the same time. We investigated the impact of various concentrations of three commonly used immunosuppressive compounds—cyclosporin A (CsA), methylprednisolone (mPRED), and mycophenolic acid (MPA)—on the growth and viability of five clinically important Aspergillus species. Methods included disc diffusion, optical density of mycelium, and viability assays such as XTT. MPA and CsA had a species-specific and dose-dependent inhibitory effect on the growth of all Aspergillus spp. tested, although growth inhibition by MPA was highest in A. niger, A. flavus and A. brasiliensis. Both agents exhibited species-specific hyphal damage, which was higher when the immunosuppressants were added to growing conidia than to mycelium. In contrast, mPRED increased the growth of A. niger, but had no major impact on the growth and viability of any of the other Aspergillus species tested. Our findings may help to better understand the interaction of drugs with Aspergillus species and ultimately may have an impact on individualizing immunosuppressive therapy. Full article
(This article belongs to the Section Human Pathogens)
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12 pages, 1066 KiB  
Article
Genetic Diversity among Pseudorabies Viruses Isolated from Dogs in France from 2006 to 2018
by Céline Deblanc, Aurélie Oger, Gaëlle Simon and Marie-Frédérique Le Potier
Pathogens 2019, 8(4), 266; https://doi.org/10.3390/pathogens8040266 - 26 Nov 2019
Cited by 14 | Viewed by 2792
Abstract
Pseudorabies (PR), also known as Aujeszky’s disease, is an economically important disease for the pig industry. It has been eradicated in domestic pigs in many European countries, including France, but its causative agent—Suid Herpesvirus 1—is still circulating in wild boars. The risk of [...] Read more.
Pseudorabies (PR), also known as Aujeszky’s disease, is an economically important disease for the pig industry. It has been eradicated in domestic pigs in many European countries, including France, but its causative agent—Suid Herpesvirus 1—is still circulating in wild boars. The risk of endemic PR in wild fauna lies in reintroducing the virus among domestic pigs and transmitting it to other mammals, especially hunting dogs for which the disease is rapidly fatal. As such infections are regularly reported in France, this study genetically characterized canine PR virus strains in the country to obtain information on their diversity and evolution. Partial sequencing of the glycoprotein C-encoding gene from 55 virus strains isolated from dogs between 2006 and 2018 showed that 14 strains belonged to genotype I-clade A and another 38 to genotype I-clade B, two clades usually reported in Western Europe. More surprisingly, three strains were found to belong to genotype II, suggesting an Asian origin. Genotype I-clade A strains exhibited the highest diversity as five geographically segregated genogroups were identified. Full article
(This article belongs to the Special Issue Pseudorabies Virus Infections)
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21 pages, 8574 KiB  
Article
Entry of Scotophilus Bat Coronavirus-512 and Severe Acute Respiratory Syndrome Coronavirus in Human and Multiple Animal Cells
by Yi-Ning Chen, Hsiao-Chin Hsu, Sheng-Wei Wang, Hao-Chiang Lien, Hsin-Ti Lu and Sheng-Kai Peng
Pathogens 2019, 8(4), 259; https://doi.org/10.3390/pathogens8040259 - 22 Nov 2019
Cited by 7 | Viewed by 7233
Abstract
Bats are natural reservoirs of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV). Scotophilus bat CoV-512 demonstrates potential for cross-species transmission because its viral RNA and specific antibodies have been detected in three bat species of Taiwan. Understanding [...] Read more.
Bats are natural reservoirs of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV). Scotophilus bat CoV-512 demonstrates potential for cross-species transmission because its viral RNA and specific antibodies have been detected in three bat species of Taiwan. Understanding the cell tropism of Scotophilus bat CoV-512 is the first step for studying the mechanism of cross-species transmission. In this study, a lentivirus-based pseudovirus was produced using the spike (S) protein of Scotophilus bat CoV-512 or SARS-CoV as a surface protein to test the interaction between coronaviral S protein and its cell receptor on 11 different cells. Susceptible cells expressed red fluorescence protein (RFP) after the entry of RFP-bound green fluorescence protein (GFP)-fused S protein of Scotophilus bat CoV-512 (RFP-Sco-S-eGFP) or RFP-SARS-S pseudovirus, and firefly luciferase (FLuc) activity expressed by cells infected with FLuc-Sco-S-eGFP or FLuc-SARS-S pseudovirus was quantified. Scotophilus bat CoV-512 pseudovirus had significantly higher entry efficiencies in Madin Darby dog kidney epithelial cells (MDCK), black flying fox brain cells (Pabr), and rat small intestine epithelial cells (IEC-6). SARS-CoV pseudovirus had significantly higher entry efficiencies in human embryonic kidney epithelial cells (HEK-293T), pig kidney epithelial cells (PK15), and MDCK cells. These findings demonstrated that Scotophilus bat CoV-512 had a broad host range for cross-species transmission like SARS-CoV. Full article
(This article belongs to the Section Animal Pathogens)
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41 pages, 6933 KiB  
Article
Genome-Wide Analyses Revealed Remarkable Heterogeneity in Pathogenicity Determinants, Antimicrobial Compounds, and CRISPR-Cas Systems of Complex Phytopathogenic Genus Pectobacterium
by Dario Arizala and Mohammad Arif
Pathogens 2019, 8(4), 247; https://doi.org/10.3390/pathogens8040247 - 20 Nov 2019
Cited by 22 | Viewed by 5567
Abstract
The Pectobacterium genus comprises pectolytic enterobacteria defined as the causal agents of soft rot, blackleg, and aerial stem rot diseases of potato and economically important crops. In this study, we undertook extensive genome-wide comparative analyses of twelve species that conform the Pectobacterium genus. [...] Read more.
The Pectobacterium genus comprises pectolytic enterobacteria defined as the causal agents of soft rot, blackleg, and aerial stem rot diseases of potato and economically important crops. In this study, we undertook extensive genome-wide comparative analyses of twelve species that conform the Pectobacterium genus. Bioinformatics approaches outlined a low nucleotide identity of P. parmentieri and P. wasabiae with other species, while P. carotovorum subsp. odoriferum was shown to harbor numerous pseudogenes, which suggests low coding capacity and genomic degradation. The genome atlases allowed for distinguishing distinct DNA structures and highlighted suspicious high transcription zones. The analyses unveiled a noteworthy heterogeneity in the pathogenicity determinants. Specifically, phytotoxins, polysaccharides, iron uptake systems, and the type secretion systems III–V were observed in just some species. Likewise, a comparison of gene clusters encoding antimicrobial compounds put in evidence for high conservation of carotovoricin, whereas a few species possessed the phenazine, carbapenem, and carocins. Moreover, three clustered regularly interspaced short palindromic repeats-Cas (CRISPR-Cas) systems: I-E, I-F, and III-A were identified. Surrounding some CRISPR-Cas regions, different toxin and antitoxin systems were found, which suggests bacterial suicide in the case of an immune system failure. Multiple whole-genome alignments shed light on to the presence of a novel cellobiose phosphotransferase system (PTS) exclusive to P. parmenteri, and an unreported T5SS conserved in almost all species. Several regions that were associated with virulence, microbe antagonism, and adaptive immune systems were predicted within genomic islands, which underscored the essential role that horizontal gene transfer has imparted in the dynamic evolution and speciation of Pectobacterium species. Overall, the results decipher the different strategies that each species has developed to infect their hosts, outcompete for food resources, and defend against bacteriophages. Our investigation provides novel genetic insights that will assist in understanding the pathogenic lifestyle of Pectobacterium, a genus that jeopardizes the agriculture sustainability of important crops worldwide. Full article
(This article belongs to the Section Plant Pathogens)
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14 pages, 1981 KiB  
Article
LmxM.22.0250-Encoded Dual Specificity Protein/Lipid Phosphatase Impairs Leishmania mexicana Virulence In Vitro
by Natalya Kraeva, Tereza Leštinová, Aygul Ishemgulova, Karolina Majerová, Anzhelika Butenko, Slavica Vaselek, Julia Bespyatykh, Arzuv Charyyeva, Tatiana Spitzová, Alexei Yu. Kostygov, Julius Lukeš, Petr Volf, Jan Votýpka and Vyacheslav Yurchenko
Pathogens 2019, 8(4), 241; https://doi.org/10.3390/pathogens8040241 - 17 Nov 2019
Cited by 11 | Viewed by 3017
Abstract
Protein phosphorylation/dephosphorylation is an important regulatory mechanism that controls many key physiological processes. Numerous pathogens successfully use kinases and phosphatases to internalize, replicate, and survive, modifying the host′s phosphorylation profile or signal transduction pathways. Multiple phosphatases and kinases from diverse bacterial pathogens have [...] Read more.
Protein phosphorylation/dephosphorylation is an important regulatory mechanism that controls many key physiological processes. Numerous pathogens successfully use kinases and phosphatases to internalize, replicate, and survive, modifying the host′s phosphorylation profile or signal transduction pathways. Multiple phosphatases and kinases from diverse bacterial pathogens have been implicated in human infections before. In this work, we have identified and characterized the dual specificity protein/lipid phosphatase LmDUSP1 as a novel virulence factor governing Leishmania mexicana infection. The LmDUSP1-encoding gene (LmxM.22.0250 in L. mexicana) has been acquired from bacteria via horizontal gene transfer. Importantly, its orthologues have been associated with virulence in several bacterial species, such as Mycobacterium tuberculosis and Listeria monocytogenes. Leishmania mexicana with ablated LmxM.22.0250 demonstrated severely attenuated virulence in the experimental infection of primary mouse macrophages, suggesting that this gene facilitates Leishmania pathogenicity in vertebrates. Despite significant upregulation of LmxM.22.0250 expression in metacyclic promastigotes, its ablation did not affect the ability of mutant cells to differentiate into virulent stages in insects. It remains to be further investigated which specific biochemical pathways involve LmDUSP1 and how this facilitates the parasite′s survival in the host. One of the interesting possibilities is that LmDUSP1 may target host′s substrate(s), thereby affecting its signal transduction pathways. Full article
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12 pages, 1743 KiB  
Article
A Single and Un-Adjuvanted Dose of a Chimpanzee Adenovirus-Vectored Vaccine against Chikungunya Virus Fully Protects Mice from Lethal Disease
by Rafael Kroon Campos, Lorena Preciado-Llanes, Sasha R. Azar, Cesar Lopez-Camacho, Arturo Reyes-Sandoval and Shannan L. Rossi
Pathogens 2019, 8(4), 231; https://doi.org/10.3390/pathogens8040231 - 12 Nov 2019
Cited by 20 | Viewed by 4958
Abstract
The mosquito-borne chikungunya virus (CHIKV) has become a major global health problem. Upon infection, chikungunya fever (CHIKF) can result in long-term joint pain and arthritis, and despite intense research, no licensed vaccine for CHIKV is available. We have developed two recombinant chimpanzee adenovirus-vectored [...] Read more.
The mosquito-borne chikungunya virus (CHIKV) has become a major global health problem. Upon infection, chikungunya fever (CHIKF) can result in long-term joint pain and arthritis, and despite intense research, no licensed vaccine for CHIKV is available. We have developed two recombinant chimpanzee adenovirus-vectored vaccines (ChAdOx1) that induce swift and robust anti-CHIKV immune responses with a single dose, without the need for adjuvants or booster vaccines. Here, we report the vaccines’ protective efficacies against CHIKV infection in a lethal A129 mouse model. Our results indicate that a single, un-adjuvanted ChAdOx1 Chik or ChAdOx1 Chik ΔCap dose provided complete protection against a lethal virus challenge and prevented CHIKV-associated severe inflammation. These candidate vaccines supported survival equal to the attenuated 181/25 CHIKV reference vaccine but without the vaccine-related side effects, such as weight loss. Vaccination with either ChAdOx1 Chik or ChAdOx1 Chik ΔCap resulted in high titers of neutralizing antibodies that are associated with protection, indicating that the presence of the capsid within the vaccine construct may not be essential to afford protection under the conditions tested. We conclude that both replication-deficient ChAdOx1 Chik vaccines are safe even when used in A129 mice and afford complete protection from a lethal challenge. Full article
(This article belongs to the Special Issue Vaccines against Alphaviruses and Flaviviruses)
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9 pages, 1357 KiB  
Review
West Nile Virus Induced Cell Death in the Central Nervous System
by Bi-Hung Peng and Tian Wang
Pathogens 2019, 8(4), 215; https://doi.org/10.3390/pathogens8040215 - 01 Nov 2019
Cited by 23 | Viewed by 3893
Abstract
West Nile virus (WNV), a mosquito-borne, single-stranded flavivirus, has caused annual outbreaks of viral encephalitis in the United States since 1999. The virus induces acute infection with a clinical spectrum ranging from a mild flu-like febrile symptom to more severe neuroinvasive conditions, including [...] Read more.
West Nile virus (WNV), a mosquito-borne, single-stranded flavivirus, has caused annual outbreaks of viral encephalitis in the United States since 1999. The virus induces acute infection with a clinical spectrum ranging from a mild flu-like febrile symptom to more severe neuroinvasive conditions, including meningitis, encephalitis, acute flaccid paralysis, and death. Some WNV convalescent patients also developed long-term neurological sequelae. Neither the treatment of WNV infection nor an approved vaccine is currently available for humans. Neuronal death in the central nervous system (CNS) is a hallmark of WNV-induced meningitis and encephalitis. However, the underlying mechanisms of WNV-induced neuronal damage are not well understood. In this review, we discuss current findings from studies of WNV infection in vitro in the CNS resident cells and the in vivo animal models, and provide insights into WNV-induced neuropathogenesis. Full article
(This article belongs to the Special Issue Pathogenesis of West Nile Virus)
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12 pages, 5962 KiB  
Article
Zebrafish are Resistant to Staphylococcus aureus Endophthalmitis
by Frank Mei, Matthew Rolain, Xiao Yi Zhou, Pawan Kumar Singh, Ryan Thummel and Ashok Kumar
Pathogens 2019, 8(4), 207; https://doi.org/10.3390/pathogens8040207 - 26 Oct 2019
Cited by 5 | Viewed by 4956
Abstract
Gram-positive bacteria remain the leading cause of endophthalmitis, a blinding infectious disease of the eye. Murine models have been widely used for understanding the pathogenesis of bacterial endophthalmitis. In this study, we sought to develop an alternative zebrafish (Danio rerio) model [...] Read more.
Gram-positive bacteria remain the leading cause of endophthalmitis, a blinding infectious disease of the eye. Murine models have been widely used for understanding the pathogenesis of bacterial endophthalmitis. In this study, we sought to develop an alternative zebrafish (Danio rerio) model for Staphylococcus aureus and compare the disease pathobiology to a murine model. Endophthalmitis was induced in zebrafish and C57BL/6 mice through the intravitreal injection of S. aureus. Disease progression was monitored by assessing corneal haze, opacity, bacterial burden, and retinal histology. Our results demonstrated that, unlike the murine models, zebrafish maintained ocular integrity, corneal transparency, and retinal architecture. We found that the zebrafish was capable of clearing S. aureus from the eye via transport through retinal vessels and the optic nerve and by mounting a monocyte/macrophage response beginning at 8 hour post-infection (hpi). The bacterial burden increased up to 8 hpi and significantly decreased thereafter. An assessment of the innate retinal response revealed the induced expression of Il-1β and Il-6 transcripts. Collectively, our study shows that unlike the murine model, zebrafish do not develop endophthalmitis and rapidly clear the pathogen. Hence, a better understanding of the zebrafish protective ocular innate response may provide new insights into the pathobiology of bacterial endophthalmitis. Full article
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11 pages, 1929 KiB  
Case Report
Taxonomical and Functional Assessment of the Endometrial Microbiota in A Context of Recurrent Reproductive Failure: A Case Report
by Iolanda Garcia-Grau, David Perez-Villaroya, Davide Bau, Marta Gonzalez-Monfort, Felipe Vilella, Inmaculada Moreno and Carlos Simon
Pathogens 2019, 8(4), 205; https://doi.org/10.3390/pathogens8040205 - 24 Oct 2019
Cited by 39 | Viewed by 5723
Abstract
Investigation of the microbial community in the female reproductive tract has revealed that the replacement of a community dominated by Lactobacillus with pathogenic bacteria may be associated with implantation failure or early spontaneous abortion in patients undergoing assisted reproductive technology (ART) treatment. Herein [...] Read more.
Investigation of the microbial community in the female reproductive tract has revealed that the replacement of a community dominated by Lactobacillus with pathogenic bacteria may be associated with implantation failure or early spontaneous abortion in patients undergoing assisted reproductive technology (ART) treatment. Herein we describe taxonomically and functionally the endometrial microbiome of an infertile patient with repeated reproductive failures (involving an ectopic pregnancy and two clinical miscarriages). The microbiological follow-up is presented over 18-month in which the microbiota was evaluated in six endometrial fluid samples. The microbial profile of 16S rRNA gene sequencing showed a persistent infection with Gardnerella and other bacterial taxa such as Atopobium and Bifidobacterium. In addition, taxonomic and functional analysis by whole metagenome sequencing in the endometrial fluid sample collected before one clinical miscarriage suggested the presence of multiple Gardnerella vaginalis clades with a greater abundance of clade 4, usually associated with metronidazole resistance. These results revealed a persistent G. vaginalis endometrial colonization presenting genetic features consistent with antimicrobial resistance, biofilm formation, and other virulence factors, which could be related to the reproductive failure observed. Full article
(This article belongs to the Section Human Pathogens)
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34 pages, 4778 KiB  
Article
An Acute Stress Model in New Zealand White Rabbits Exhibits Altered Immune Response to Infection with West Nile Virus
by Willy W. Suen, Mitchell Imoda, Albert W. Thomas, Nur N.B.M. Nasir, Nawaporn Tearnsing, Wenqi Wang and Helle Bielefeldt-Ohmann
Pathogens 2019, 8(4), 195; https://doi.org/10.3390/pathogens8040195 - 18 Oct 2019
Cited by 4 | Viewed by 2973
Abstract
The immune competence of an individual is a major determinant of morbidity in West Nile virus (WNV)-infection. Previously, we showed that immunocompetent New Zealand White rabbits (NZWRs; Oryctolagus cuniculus) are phenotypically resistant to WNV-induced disease, thus presenting a suitable model for study [...] Read more.
The immune competence of an individual is a major determinant of morbidity in West Nile virus (WNV)-infection. Previously, we showed that immunocompetent New Zealand White rabbits (NZWRs; Oryctolagus cuniculus) are phenotypically resistant to WNV-induced disease, thus presenting a suitable model for study of virus-control mechanisms. The current study used corticosteroid-treated NZWRs to model acute “stress”-related immunosuppression. Maximal effects on immune parameters were observed on day 3 post dexamethasone-treatment (pdt). However, contrary to our hypothesis, intradermal WNV challenge at this time pdt produced significantly lower viremia 1 day post-infection (dpi) compared to untreated controls, suggestive of changes to antiviral control mechanisms. To examine this further, RNAseq was performed on RNA extracted from draining lymph node—the first site of virus replication and immune detection. Unaffected by dexamethasone-treatment, an early antiviral response, primarily via interferon (IFN)-I, and induction of a range of known and novel IFN-stimulated genes, was observed. However, treatment was associated with expression of a different repertoire of IFN-α-21-like and IFN-ω-1-like subtypes on 1 dpi, which may have driven the different chemokine response on 3 dpi. Ongoing expression of Toll-like receptor-3 and transmembrane protein-173/STING likely contributed to signaling of the treatment-independent IFN-I response. Two novel genes (putative HERC6 and IFIT1B genes), and the SLC16A5 gene were also highlighted as important component of the transcriptomic response. Therefore, the current study shows that rabbits are capable of restricting WNV replication and dissemination by known and novel robust antiviral mechanisms despite environmental challenges such as stress. Full article
(This article belongs to the Special Issue Pathogenesis of West Nile Virus)
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9 pages, 2769 KiB  
Review
Formation and Maintenance of Tissue Resident Memory CD8+ T Cells after Viral Infection
by David J. Topham, Emma C. Reilly, Kris Lambert Emo and Mike Sportiello
Pathogens 2019, 8(4), 196; https://doi.org/10.3390/pathogens8040196 - 18 Oct 2019
Cited by 6 | Viewed by 3870
Abstract
Tissue resident memory (TRM) CD8 T cells comprise a memory population that forms in peripheral, non-lymphoid tissues after an infection that does not recirculate into the bloodstream or other tissues. TRM cells often recognize conserved peptide epitopes shared among different [...] Read more.
Tissue resident memory (TRM) CD8 T cells comprise a memory population that forms in peripheral, non-lymphoid tissues after an infection that does not recirculate into the bloodstream or other tissues. TRM cells often recognize conserved peptide epitopes shared among different strains of a pathogen and so offer a protective role upon secondary encounter with the same or related pathogens. Several recent studies have begun to shed light on the intrinsic and extrinsic factors regulating TRM. In addition, work is being done to understand how canonical “markers” of TRM actually affect the function of these cells. Many of these markers regulate the generation or persistence of these TRM cells, an important point of study due to the differences in persistence of TRM between tissues, which may impact future vaccine development to cater towards these important differences. In this review, we will discuss recent advances in TRM biology that may lead to strategies designed to promote this important protective immune subset. Full article
(This article belongs to the Special Issue Influenza Virus and Vaccination)
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21 pages, 861 KiB  
Review
Current Understanding of West Nile Virus Clinical Manifestations, Immune Responses, Neuroinvasion, and Immunotherapeutic Implications
by Fengwei Bai, E. Ashley Thompson, Parminder J. S. Vig and A. Arturo Leis
Pathogens 2019, 8(4), 193; https://doi.org/10.3390/pathogens8040193 - 16 Oct 2019
Cited by 57 | Viewed by 11464
Abstract
West Nile virus (WNV) is the most common mosquito-borne virus in North America. WNV-associated neuroinvasive disease affects all ages, although elderly and immunocompromised individuals are particularly at risk. WNV neuroinvasive disease has killed over 2300 Americans since WNV entered into the United States [...] Read more.
West Nile virus (WNV) is the most common mosquito-borne virus in North America. WNV-associated neuroinvasive disease affects all ages, although elderly and immunocompromised individuals are particularly at risk. WNV neuroinvasive disease has killed over 2300 Americans since WNV entered into the United States in the New York City outbreak of 1999. Despite 20 years of intensive laboratory and clinical research, there are still no approved vaccines or antivirals available for human use. However, rapid progress has been made in both understanding the pathogenesis of WNV and treatment in clinical practices. This review summarizes our current understanding of WNV infection in terms of human clinical manifestations, host immune responses, neuroinvasion, and therapeutic interventions. Full article
(This article belongs to the Special Issue Pathogenesis of West Nile Virus)
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13 pages, 2346 KiB  
Article
Analysis of Resistance of Ebola Virus Glycoprotein-Driven Entry Against MDL28170, An Inhibitor of Cysteine Cathepsins
by Markus Hoffmann, Svenja Victoria Kaufmann, Carina Fischer, Wiebke Maurer, Anna-Sophie Moldenhauer and Stefan Pöhlmann
Pathogens 2019, 8(4), 192; https://doi.org/10.3390/pathogens8040192 - 15 Oct 2019
Cited by 2 | Viewed by 3638
Abstract
Ebola virus (EBOV) infection can cause severe and frequently fatal disease in human patients. The EBOV glycoprotein (GP) mediates viral entry into host cells. For this, GP depends on priming by the pH-dependent endolysosomal cysteine proteases cathepsin B (CatB) and, to a lesser [...] Read more.
Ebola virus (EBOV) infection can cause severe and frequently fatal disease in human patients. The EBOV glycoprotein (GP) mediates viral entry into host cells. For this, GP depends on priming by the pH-dependent endolysosomal cysteine proteases cathepsin B (CatB) and, to a lesser degree, cathepsin L (CatL), at least in most cell culture systems. However, there is limited information on whether and how EBOV-GP can acquire resistance to CatB/L inhibitors. Here, we addressed this question using replication-competent vesicular stomatitis virus bearing EBOV-GP. Five passages of this virus in the presence of the CatB/CatL inhibitor MDL28170 were sufficient to select resistant viral variants and sequencing revealed that all GP sequences contained a V37A mutation, which, in the context of native GP, is located in the base of the GP surface unit. In addition, some GP sequences harbored mutation S195R in the receptor-binding domain. Finally, mutational analysis demonstrated that V37A but not S195R conferred resistance against MDL28170 and other CatB/CatL inhibitors. Collectively, a single amino acid substitution in GP is sufficient to confer resistance against CatB/CatL inhibitors, suggesting that usage of CatB/CatL inhibitors for antiviral therapy may rapidly select for resistant viral variants. Full article
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17 pages, 2478 KiB  
Article
Genomic Epidemiology of Streptococcus suis Sequence Type 7 Sporadic Infections in the Guangxi Zhuang Autonomous Region of China
by Mingliu Wang, Pengcheng Du, Jianping Wang, Ruiting Lan, Jun Huang, Ming Luo, Yan Jiang, Jun Zeng, Yi Quan, Zhaohui Shi and Han Zheng
Pathogens 2019, 8(4), 187; https://doi.org/10.3390/pathogens8040187 - 12 Oct 2019
Cited by 16 | Viewed by 3558
Abstract
Streptococcus suis is an important zoonotic pathogen. Serotype 2 and sequence type (ST) 1 are the most frequently reported strains in both infected humans and pigs. ST7 is only endemic to China, and it was responsible for outbreaks in 1998 and 2005 in [...] Read more.
Streptococcus suis is an important zoonotic pathogen. Serotype 2 and sequence type (ST) 1 are the most frequently reported strains in both infected humans and pigs. ST7 is only endemic to China, and it was responsible for outbreaks in 1998 and 2005 in China. In the present study, 38 sporadic ST7 S. suis strains, which mostly caused sepsis, were collected from patients in the Guangxi Zhuang Autonomous Region (GX) between 2007 and 2018. Of 38 sporadic ST7 strains, serotype 14 was the most frequent (27 strains, 71.1%), followed by serotype 2 (11 strains, 28.9%). The phylogenetic structure of the ST7 population, including epidemic and sporadic ST7 strains, was constructed using mutational single-nucleotide polymorphisms (SNPs). High diversity within the ST7 population was revealed and divided into five lineages. Only one sporadic ST7 strain, GX14, from a Streptococcal toxic-shock-like syndrome (STSLS) patient was clustered into the same lineage as the epidemic strains. GX14 and the epidemic strains diverged in 1974. The sporadic ST7 strains of GX were mainly clustered into lineage 5, which emerged in 1980. Comparing to genome of epidemic strain, the major differences in genome of sporadic ST7 strains of GX was the absence of 89 kb pathogenicity island (PAI) specific to epidemic strain and insertion of 128 kb ICE_phage tandem MGE or ICE portion of the MGE. These mobile elements play a significant role in the horizontal transfer of antibiotic resistance genes in sporadic ST7 strains. Our results enhanced the understanding of the evolution of the ST7 strains and their ability to cause life-threatening infections in humans. Full article
(This article belongs to the Special Issue Update on Streptococcus suis Research and Prevention in the Era of Antibiotic Restriction - 4th International Workshop on Streptococcus suis)
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15 pages, 3967 KiB  
Article
Whole Transcriptome Analyses Reveal Differential mRNA and microRNA Expression Profiles in Primary Human Dermal Fibroblasts Infected with Clinical or Vaccine Strains of Varicella Zoster Virus
by Soo-Jin Oh, Sooyeon Lim, Moon Jung Song, Jin Hyun Ahn, Chan Hee Lee and Ok Sarah Shin
Pathogens 2019, 8(4), 183; https://doi.org/10.3390/pathogens8040183 - 10 Oct 2019
Cited by 14 | Viewed by 3647
Abstract
Licensed live attenuated vaccines have been developed to prevent varicella zoster virus (VZV) infection, which causes chickenpox and shingles. The genomic sequences of both clinical- and vaccine-derived VZV strains have been analyzed previously. To further characterize the molecular signatures and complexity of wildtype [...] Read more.
Licensed live attenuated vaccines have been developed to prevent varicella zoster virus (VZV) infection, which causes chickenpox and shingles. The genomic sequences of both clinical- and vaccine-derived VZV strains have been analyzed previously. To further characterize the molecular signatures and complexity of wildtype (clinical) versus attenuated (vaccine-derived) VZV-mediated host cellular responses, we performed high-throughput next generation sequencing to quantify and compare the expression patterns of mRNAs and microRNAs (miRNAs) in primary human dermal fibroblasts (HDFs) infected with wildtype (YC01 low passage) and attenuated (YC01 high passage, SuduVax, and VarilRix) VZV strains. 3D-multidimensional scaling of the differentially expressed genes demonstrated the distinct grouping of wildtype and attenuated strains. In particular, we observed that HDFs infected with attenuated strains had more differentially expressed genes (DEGs) involved in the retinoic-acid inducible gene–I-like receptor and interferon-mediated signaling pathways compared with wildtype strains. Additionally, miRNA expression patterns were profiled following the infection of HDFs with VZV. Small RNA sequencing identified that several miRNAs were upregulated, including miR-146a-5p, which has been associated with other herpesvirus infections, whereas let-7a-3p was downregulated in both wildtype and attenuated VZV-infected cells. This study identified genes and miRNAs that may be essential in VZV pathogenesis. Full article
(This article belongs to the Special Issue Human Herpesviruses: Diversity and Disease)
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22 pages, 906 KiB  
Review
Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans
by Aitor Nogales and Marta L. DeDiego
Pathogens 2019, 8(4), 168; https://doi.org/10.3390/pathogens8040168 - 30 Sep 2019
Cited by 26 | Viewed by 7227
Abstract
A large number of human genes associated with viral infections contain single nucleotide polymorphisms (SNPs), which represent a genetic variation caused by the change of a single nucleotide in the DNA sequence. SNPs are located in coding or non-coding genomic regions and can [...] Read more.
A large number of human genes associated with viral infections contain single nucleotide polymorphisms (SNPs), which represent a genetic variation caused by the change of a single nucleotide in the DNA sequence. SNPs are located in coding or non-coding genomic regions and can affect gene expression or protein function by different mechanisms. Furthermore, they have been linked to multiple human diseases, highlighting their medical relevance. Therefore, the identification and analysis of this kind of polymorphisms in the human genome has gained high importance in the research community, and an increasing number of studies have been published during the last years. As a consequence of this exhaustive exploration, an association between the presence of some specific SNPs and the susceptibility or severity of many infectious diseases in some risk population groups has been found. In this review, we discuss the relevance of SNPs that are important to understand the pathology derived from influenza A virus (IAV) infections in humans and the susceptibility of some individuals to suffer more severe symptoms. We also discuss the importance of SNPs for IAV vaccine effectiveness. Full article
(This article belongs to the Special Issue Influenza Virus and Vaccination)
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13 pages, 3321 KiB  
Article
Atypical Dermatophytosis in 12 North American Porcupines (Erethizon dorsatum) from the Northeastern United States 2010–2017
by David B. Needle, Robert Gibson, Nicholas A. Hollingshead, Inga F. Sidor, Nicholas J. Marra, Derek Rothenheber, Anil J. Thachil, Bryce J. Stanhope, Brian A. Stevens, Julie C. Ellis, Shelley Spanswick, Maureen Murray and Laura B. Goodman
Pathogens 2019, 8(4), 171; https://doi.org/10.3390/pathogens8040171 - 30 Sep 2019
Cited by 7 | Viewed by 4218
Abstract
Twelve wild North American porcupines (Erethizon dorsatum) out of a total of 44 of this species examined in an 8-year period were diagnosed with dermatopathies while being cared for at two wildlife rehabilitation clinics. Biopsy and necropsy were performed on seven [...] Read more.
Twelve wild North American porcupines (Erethizon dorsatum) out of a total of 44 of this species examined in an 8-year period were diagnosed with dermatopathies while being cared for at two wildlife rehabilitation clinics. Biopsy and necropsy were performed on seven and five animals, respectively. Atypical dermatophytosis was diagnosed in all cases. Lesions consisted of diffuse severe epidermal hyperkeratosis and mild hyperplasia with mild lymphoplasmacytic dermatitis and no folliculitis. Dermatophytes were noted histologically as hyphae and spores in hair shafts, and follicular and epidermal keratin. Trichophyton sp. was grown in 5/6 animals where culture was performed, with a molecular diagnosis of Arthroderma benhamiae/Trichophyton mentagrophytes in these five cases. Metagenomic analysis of formalin-fixed paraffin-embedded tissue samples from three cases identified fungi from 17 orders in phyla Basidiomycota and Ascomycota. Alteration of therapy from ketaconazole, which was unsuccessful in four out of five early cases, to terbinafine or nitraconazole led to the resolution of disease and recovery to release in four subsequent animals. In all, six animals were euthanized or died due to dermatopathy, no cases resolved spontaneously, and six cases were resolved with therapy. The work we present demonstrates an atypical lesion and anatomical distribution due to dermatophytosis in a series of free-ranging wild porcupines and the successful development of novel techniques for extracting and sequencing nucleic acids from fungus in archival formalin-fixed paraffin-embedded animal tissue. Full article
(This article belongs to the Section Animal Pathogens)
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13 pages, 1114 KiB  
Review
Role of Memory B Cells in Hemagglutinin-Specific Antibody Production Following Human Influenza A Virus Infection
by Mark Y. Sangster, Phuong Q. T. Nguyen and David J. Topham
Pathogens 2019, 8(4), 167; https://doi.org/10.3390/pathogens8040167 - 28 Sep 2019
Cited by 18 | Viewed by 6256
Abstract
When influenza A virus infects an immune individual, preexisting memory B cell (MBC) activation and rapid anamnestic antibody production plays a key role in viral clearance. The most effective neutralizing antibodies target the antigenically variable head of the viral hemagglutinin (HA); antibodies against [...] Read more.
When influenza A virus infects an immune individual, preexisting memory B cell (MBC) activation and rapid anamnestic antibody production plays a key role in viral clearance. The most effective neutralizing antibodies target the antigenically variable head of the viral hemagglutinin (HA); antibodies against the conserved HA stalk provide broader but less potent protection. In this review, we provide a comprehensive picture of an adult’s HA-specific antibody response to influenza virus infection. The process is followed from preexisting HA-specific MBC activation and rapid production of anti-HA antibodies, through to germinal center seeding and adaptation of the response to novel features of the HA. A major focus of the review is the role of competition between preexisting MBCs in determining the character of the HA-reactive antibody response. HA novelty modifies this competition and can shift the response from the immunodominant head to the stalk. We suggest that antibodies resulting from preexisting MBC activation are important regulators of anti-HA antibody production and play a role in positive selection of germinal center B cells reactive to novel HA epitopes. Our review also considers the role of MBCs in the effects of early-life imprinting on HA head- and stalk-specific antibody responses to influenza infection. An understanding of the processes described in this review will guide development of vaccination strategies that provide broadly effective protection. Full article
(This article belongs to the Special Issue Influenza Virus and Vaccination)
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15 pages, 947 KiB  
Article
Prevalence of Various Vaccine Candidate Proteins in Clinical Isolates of Streptococcus pneumoniae: Characterization of the Novel Pht Fusion Proteins PhtA/B and PhtA/D
by Mitsuyo Kawaguchiya, Noriko Urushibara, Meiji Soe Aung, Masaaki Shinagawa, Satoshi Takahashi and Nobumichi Kobayashi
Pathogens 2019, 8(4), 162; https://doi.org/10.3390/pathogens8040162 - 24 Sep 2019
Cited by 8 | Viewed by 2943
Abstract
Pneumococcal proteins unrelated to serotypes are considered to be candidates of antigens in next-generation vaccines. In the present study, the prevalence of vaccine candidate protein genes, along with serotypes and antimicrobial resistance determinants, was investigated in a total of 57 isolates obtained from [...] Read more.
Pneumococcal proteins unrelated to serotypes are considered to be candidates of antigens in next-generation vaccines. In the present study, the prevalence of vaccine candidate protein genes, along with serotypes and antimicrobial resistance determinants, was investigated in a total of 57 isolates obtained from a tertiary care hospital in Japan. All of the pediatric isolates and 76.6% of the adult isolates did not belong to PCV13 (a 13-valent pneumococcal conjugate vaccine) serotypes, and 70.2% of all isolates showed multidrug resistance. All of the isolates had ply, pavA, nanA, and nanB, and high prevalence was noted for the pspA and pspC genes (96.5% and 78.9%, respectively). Detection rates for the pneumococcal histidine triad protein (Pht) genes phtA, phtB, phtD, and phtE were 49.1%, 26.3%, 61.4%, and 100%, respectively. Two fusion-type genes, phtA/B and phtA/D, were identified, with a prevalence of 36.9% and 14.0%, respectively. These fusion types showed 78.1–90.0% nucleotide sequence identity with phtA, phtB, and phtD. The most prevalent pht profile was phtA + phtD + phtE (26.3%), followed by phtA/B + phtE (19.3%) and phtA/B + phtD + phtE (17.5%), while pht profiles including phtD and/or phtA/phtD were found in 71.9% of isolates. The present study revealed the presence of two fusion types of Pht and their unexpectedly high prevalence. These fusion types, as well as PhtA and PhtB, contained sequences similar to the B cell epitopes that have been previously reported for PhtD. Full article
(This article belongs to the Section Human Pathogens)
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12 pages, 4546 KiB  
Article
New Taxon-Specific Heterobasidion PCR Primers Detect and Differentiate North American Heterobasidion spp. in Various Substrates and Led to the Discovery of Heterobasidion irregulare in British Columbia, Canada
by Simon Francis Shamoun, Craig Hammett, Grace Sumampong, Xiang Li and Matteo Garbelotto
Pathogens 2019, 8(3), 156; https://doi.org/10.3390/pathogens8030156 - 18 Sep 2019
Cited by 3 | Viewed by 4354
Abstract
Heterobasidion annosum sensu lato is a species complex of pathogenic white-rot wood decay fungi which cause root and butt rot in conifer and hardwood species across the Northern hemisphere. Annual losses to forest managers are valued in the billions of dollars, due to [...] Read more.
Heterobasidion annosum sensu lato is a species complex of pathogenic white-rot wood decay fungi which cause root and butt rot in conifer and hardwood species across the Northern hemisphere. Annual losses to forest managers are valued in the billions of dollars, due to tree mortality, reduction in timber yield, and wood decay. In North America, H. irregulare and H. occidentale have a partially overlapping host and geographic range, cause similar disease symptoms and produce similar fruiting bodies, making discrimination between the two of them often difficult. We developed two sets of primers that bind specifically to conserved, but species-specific portions of glyceraldehyde 3-phosphate dehydrogenase and elongation factor 1α alleles. The method is sensitive enough to detect either species from infected wood. Analysis of North American isolates has further clarified the distribution of both species on this continent, including the detection of H. irregulare for the first time on ponderosa pine (Pinus ponderosa) and eastern white pine (Pinus strobus) in British Columbia. This method has the potential to be a valuable tool for the detection of the pathogen in exported/imported wood products, as well as for the further identification and assessment of the distribution of North American Heterobasidion species. Full article
(This article belongs to the Section Plant Pathogens)
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10 pages, 1001 KiB  
Review
Role of Endoplasmic Reticulum-Associated Proteins in Flavivirus Replication and Assembly Complexes
by Hussin A. Rothan and Mukesh Kumar
Pathogens 2019, 8(3), 148; https://doi.org/10.3390/pathogens8030148 - 12 Sep 2019
Cited by 30 | Viewed by 5684
Abstract
Flavivirus replication in host cells requires the formation of replication and assembly complexes on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. These complexes consist of an ER membrane, viral proteins, and host proteins. Genome-wide investigations have identified a number of ER [...] Read more.
Flavivirus replication in host cells requires the formation of replication and assembly complexes on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. These complexes consist of an ER membrane, viral proteins, and host proteins. Genome-wide investigations have identified a number of ER multiprotein complexes as vital factors for flavivirus replication. The detailed mechanisms of the role of ER complexes in flavivirus replication are still largely elusive. This review highlights the fact that the ER multiprotein complexes are crucial for the formation of flavivirus replication and assembly complexes, and the ER complexes could be considered as a target for developing successful broad-spectrum anti-flavivirus drugs. Full article
(This article belongs to the Special Issue Current Advances in Flavivirus Research)
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14 pages, 3346 KiB  
Article
A Single Dose of Modified Vaccinia Ankara Expressing Lassa Virus-like Particles Protects Mice from Lethal Intra-cerebral Virus Challenge
by Maria S. Salvato, Arban Domi, Camila Guzmán-Cardozo, Sandra Medina-Moreno, Juan Carlos Zapata, Haoting Hsu, Nathanael McCurley, Rahul Basu, Mary Hauser, Michael Hellerstein and Farshad Guirakhoo
Pathogens 2019, 8(3), 133; https://doi.org/10.3390/pathogens8030133 - 28 Aug 2019
Cited by 19 | Viewed by 8138
Abstract
Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report [...] Read more.
Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report construction, characterization, and preclinical efficacy of a novel recombinant vaccine candidate GEO-LM01. Constructed in the Modified Vaccinia Ankara (MVA) vector, GEO-LM01 expresses the glycoprotein precursor (GPC) and zinc-binding matrix protein (Z) from the prototype Josiah strain lineage IV. When expressed together, GP and Z form Virus-Like Particles (VLPs) in cell culture. Immunogenicity and efficacy of GEO-LM01 was tested in a mouse challenge model. A single intramuscular dose of GEO-LM01 protected 100% of CBA/J mice challenged with a lethal dose of ML29, a Mopeia/Lassa reassortant virus, delivered directly into the brain. In contrast, all control animals died within one week. The vaccine induced low levels of antibodies but Lassa-specific CD4+ and CD8+ T cell responses. This is the first report showing that a single dose of a replication-deficient MVA vector can confer full protection against a lethal challenge with ML29 virus. Full article
(This article belongs to the Special Issue Lassa Fever: Viral Replication, Disease Pathogenesis, and Host Immune Modulations)
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28 pages, 1438 KiB  
Review
Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome
by Israr Khan, Naeem Ullah, Lajia Zha, Yanrui Bai, Ashiq Khan, Tang Zhao, Tuanjie Che and Chunjiang Zhang
Pathogens 2019, 8(3), 126; https://doi.org/10.3390/pathogens8030126 - 13 Aug 2019
Cited by 430 | Viewed by 28059
Abstract
Inflammatory bowel disease (IBD) is a chronic complex inflammatory gut pathological condition, examples of which include Crohn’s disease (CD) and ulcerative colitis (UC), which is associated with significant morbidity. Although the etiology of IBD is unknown, gut microbiota alteration (dysbiosis) is considered a [...] Read more.
Inflammatory bowel disease (IBD) is a chronic complex inflammatory gut pathological condition, examples of which include Crohn’s disease (CD) and ulcerative colitis (UC), which is associated with significant morbidity. Although the etiology of IBD is unknown, gut microbiota alteration (dysbiosis) is considered a novel factor involved in the pathogenesis of IBD. The gut microbiota acts as a metabolic organ and contributes to human health by performing various physiological functions; deviation in the gut flora composition is involved in various disease pathologies, including IBD. This review aims to summarize the current knowledge of gut microbiota alteration in IBD and how this contributes to intestinal inflammation, as well as explore the potential role of gut microbiota-based treatment approaches for the prevention and treatment of IBD. The current literature has clearly demonstrated a perturbation of the gut microbiota in IBD patients and mice colitis models, but a clear causal link of cause and effect has not yet been presented. In addition, gut microbiota-based therapeutic approaches have also shown good evidence of their effects in the amelioration of colitis in animal models (mice) and IBD patients, which indicates that gut flora might be a new promising therapeutic target for the treatment of IBD. However, insufficient data and confusing results from previous studies have led to a failure to define a core microbiome associated with IBD and the hidden mechanism of pathogenesis, which suggests that well-designed randomized control trials and mouse models are required for further research. In addition, a better understanding of this ecosystem will also determine the role of prebiotics and probiotics as therapeutic agents in the management of IBD. Full article
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11 pages, 6927 KiB  
Article
In Vitro Activity of Statins against Naegleria fowleri
by Aitor Rizo-Liendo, Ines Sifaoui, María Reyes-Batlle, Olfa Chiboub, Rubén L. Rodríguez-Expósito, Carlos J. Bethencourt-Estrella, Desirée San Nicolás-Hernández, Edyta B. Hendiger, Atteneri López-Arencibia, Pedro Rocha-Cabrera, José E. Piñero and Jacob Lorenzo-Morales
Pathogens 2019, 8(3), 122; https://doi.org/10.3390/pathogens8030122 - 08 Aug 2019
Cited by 22 | Viewed by 4810
Abstract
Naegleria fowleri causes a deadly disease called primary amoebic meningoencephalitis (PAM). Even though PAM is still considered a rare disease, the number of reported cases worldwide has been increasing each year. Among the factors to be considered for this, awareness about this disease, [...] Read more.
Naegleria fowleri causes a deadly disease called primary amoebic meningoencephalitis (PAM). Even though PAM is still considered a rare disease, the number of reported cases worldwide has been increasing each year. Among the factors to be considered for this, awareness about this disease, and also global warming, as these amoebae thrive in warm water bodies, seem to be the key factors. Until present, no fully effective drugs have been developed to treat PAM, and the current options are amphotericin B and miltefosine, which present side effects such as liver and kidney toxicity. Statins are able to inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is a key enzyme for the synthesis of ergosterol of the cell membrane of these amoebae. Therefore, the in vitro activity of a group of statins was tested in this study against two types of strains of Naegleria fowleri. The obtained results showed that fluvastatin was the most effective statin tested in this study and was able to eliminate these amoebae at concentrations of 0.179 ± 0.078 to 1.682 ± 0.775 µM depending on the tested strain of N. fowleri. Therefore, fluvastatin could be a potential novel therapeutic agent against this emerging pathogen. Full article
(This article belongs to the Special Issue Emerging Parasitic Protozoa)
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11 pages, 2360 KiB  
Article
Genetic Characterization of Chikungunya Virus in Field-Caught Aedes aegypti Mosquitoes Collected during the Recent Outbreaks in 2019, Thailand
by Proawpilart Intayot, Atchara Phumee, Rungfar Boonserm, Sriwatapron Sor-suwan, Rome Buathong, Supaporn Wacharapluesadee, Narisa Brownell, Yong Poovorawan and Padet Siriyasatien
Pathogens 2019, 8(3), 121; https://doi.org/10.3390/pathogens8030121 - 02 Aug 2019
Cited by 24 | Viewed by 4942
Abstract
Chikungunya virus (CHIKV) is a mosquito-borne virus belonging to the genus Alphavirus. The virus is transmitted to humans by the bite of infected female Aedes mosquitoes, primarily Aedes aegypti. CHIKV infection is spreading worldwide, and it periodically sparks new outbreaks. There [...] Read more.
Chikungunya virus (CHIKV) is a mosquito-borne virus belonging to the genus Alphavirus. The virus is transmitted to humans by the bite of infected female Aedes mosquitoes, primarily Aedes aegypti. CHIKV infection is spreading worldwide, and it periodically sparks new outbreaks. There are no specific drugs or effective vaccines against CHIKV. The interruption of pathogen transmission by mosquito control provides the only effective approach to the control of CHIKV infection. Many studies have shown that CHIKV can be transmitted among the Ae. aegypti through vertical transmission. The previous chikungunya fever outbreaks in Thailand during 2008–2009 were caused by CHIKV, the East/Central/South African (ECSA) genotype. Recently, there have been 3794 chikungunya cases in 27 provinces reported by the Bureau of Epidemiology of Health Ministry, Thailand during 1 January–16 June 2019; however, the cause of the re-emergence of CHIKV outbreaks is uncertain. Therefore, the aims of this study were to detect and analyze the genetic diversity of CHIKV infection in field-caught mosquitoes. Both female and male Ae. aegypti were collected from endemic areas of Thailand, and CHIKV detection was done by using E1-nested RT-PCR and sequencing analysis. A total of 1646 Ae. aegypti samples (900 females and 746 males) were tested. CHIKV was detected in 54 (3.28%) and 14 samples (0.85%) in female and male mosquitoes, respectively. Seventeen samples of female Ae. aegypti collected from the Ubon Ratchathani, Chiang Rai, Chiang Mai, Nakhon Sawan, and Songkhla provinces found mutation at E1: A226V. Interestingly, E1: K211E mutation was observed in 50 samples collected from Nong Khai, Bangkok, Prachuap Khiri Khan, and Krabi. In addition, the phylogenetic tree indicated that CHIKV in Ae. aegypti samples were from the Indian Ocean Clade and East/South African Clade. Both clades belong to the ECSA genotype. The information obtained from this study could be used for prediction, epidemiological study, prevention, and effective vector control of CHIKV. For instance, a novel CHIKV strain found in new areas has the potential to lead to a new outbreak. Health authorities could plan and apply control strategies more effectively given the tools provided by this research. Full article
(This article belongs to the Special Issue Chikungunya Virus Infections)
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17 pages, 9372 KiB  
Article
N-acetyl Cysteine Coated Gallium Particles Demonstrate High Potency against Pseudomonas aeruginosa PAO1
by Mikaeel Young, Ali Ozcan, Briana Lee, Tyler Maxwell, Thomas Andl, Parthiban Rajasekaran, Melanie J. Beazley, Laurene Tetard and Swadeshmukul Santra
Pathogens 2019, 8(3), 120; https://doi.org/10.3390/pathogens8030120 - 01 Aug 2019
Cited by 8 | Viewed by 3522
Abstract
Nosocomial infections pose serious health concerns with over 2 million reported annually in the United States. Many of these infections are associated with bacterial resistance to antibiotics and hence, alternative treatments are critically needed. The objective of this study was to assess the [...] Read more.
Nosocomial infections pose serious health concerns with over 2 million reported annually in the United States. Many of these infections are associated with bacterial resistance to antibiotics and hence, alternative treatments are critically needed. The objective of this study was to assess the antimicrobial efficacy of a gallium (Ga)-based particle coated with N-Acetyl Cysteine (Ga-NAC) against Pseudomonas aeruginosa PAO1. Our studies showed the Minimum Inhibitory Concentration (MIC) of PAO1 treated with Ga-NAC was 1 µg/mL. Cytotoxicity of Ga-NAC against multiple cell lines was determined with no cytotoxicity observed up to concentrations of 2000 µg/mL (metal concentration), indicating a high therapeutic window. To elucidate potential antibacterial modes of action, Inductively Coupled Plasma—Mass Spectrometry (ICP-MS), infrared spectroscopy, and atomic force microscopy (AFM) were used. The results suggest improved Ga3+ interaction with PAO1 through Ga-NAC particles. No significant change in cell membrane chemistry or roughening was detected. As cell membrane integrity remained intact, the antimicrobial mode of action was linked to cellular internalization of Ga and subsequent iron metabolic disruption. Furthermore, Ga-NAC inhibited and disrupted biofilms seen with crystal violet assay and microscopy. Our findings suggest the Ga-NAC particle can potentially be used as an alternative to antibiotics for treatment of Pseudomonas aeruginosa infections. Full article
(This article belongs to the Section Vaccines and Therapeutic Developments)
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22 pages, 1738 KiB  
Article
Multi-Lineage Evolution in Viral Populations Driven by Host Immune Systems
by Jacopo Marchi, Michael Lässig, Thierry Mora and Aleksandra M. Walczak
Pathogens 2019, 8(3), 115; https://doi.org/10.3390/pathogens8030115 - 29 Jul 2019
Cited by 9 | Viewed by 3954
Abstract
Viruses evolve in the background of host immune systems that exert selective pressure and drive viral evolutionary trajectories. This interaction leads to different evolutionary patterns in antigenic space. Examples observed in nature include the effectively one-dimensional escape characteristic of influenza A and the [...] Read more.
Viruses evolve in the background of host immune systems that exert selective pressure and drive viral evolutionary trajectories. This interaction leads to different evolutionary patterns in antigenic space. Examples observed in nature include the effectively one-dimensional escape characteristic of influenza A and the prolonged coexistence of lineages in influenza B. Here, we use an evolutionary model for viruses in the presence of immune host systems with finite memory to obtain a phase diagram of evolutionary patterns in a two-dimensional antigenic space. We find that, for small effective mutation rates and mutation jump ranges, a single lineage is the only stable solution. Large effective mutation rates combined with large mutational jumps in antigenic space lead to multiple stably co-existing lineages over prolonged evolutionary periods. These results combined with observations from data constrain the parameter regimes for the adaptation of viruses, including influenza. Full article
(This article belongs to the Special Issue Modeling Virus Dynamics and Evolution)
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