Research

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18 pages, 1909 KiB

Open AccessArticle

Expression of Bacillus cereus Virulence-Related Genes in an Ocular Infection-Related Environment

by Phillip S. Coburn, Frederick C. Miller, Morgan A. Enty, Craig Land, Austin L. LaGrow, Md Huzzatul Mursalin and Michelle C. Callegan

Microorganisms 2020, 8(4), 607; https://doi.org/10.3390/microorganisms8040607 - 22 Apr 2020

Cited by 15 | Viewed by 3740

Abstract

Bacillus cereus produces many factors linked to pathogenesis and is recognized for causing gastrointestinal toxemia and infections. B. cereus also causes a fulminant and often blinding intraocular infection called endophthalmitis. We reported that the PlcR/PapR system regulates intraocular virulence, but the specific factors [...] Read more.

Bacillus cereus produces many factors linked to pathogenesis and is recognized for causing gastrointestinal toxemia and infections. B. cereus also causes a fulminant and often blinding intraocular infection called endophthalmitis. We reported that the PlcR/PapR system regulates intraocular virulence, but the specific factors that contribute to B. cereus virulence in the eye remain elusive. Here, we compared gene expression in ex vivo vitreous humor with expression in Luria Bertani (LB) and Brain Heart Infusion (BHI) broth by RNA-Seq. The expression of several cytolytic toxins in vitreous was less than or similar to levels observed in BHI or LB. Regulators of virulence genes, including PlcR/PapR, were expressed in vitreous. PlcR/PapR was expressed at low levels, though we reported that PlcR-deficient B. cereus was attenuated in the eye. Chemotaxis and motility genes were expressed at similar levels in LB and BHI, but at low to undetectable levels in vitreous, although motility is an important phenotype for B. cereus in the eye. Superoxide dismutase, a potential inhibitor of neutrophil activity in the eye during infection, was the most highly expressed gene in vitreous. Genes previously reported to be important to intraocular virulence were expressed at low levels in vitreous under these conditions, possibly because in vivo cues are required for higher level expression. Genes expressed in vitreous may contribute to the unique virulence of B. cereus endophthalmitis, and future analysis of the B. cereus virulome in the eye will identify those expressed in vivo, which could potentially be targeted to arrest virulence. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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14 pages, 1631 KiB

Open AccessArticle

Characterization of Ocular Clinical Isolates of Pseudomonas aeruginosa from Non-Contact Lens Related Keratitis Patients from South India

by Alpana Dave, Apurwa Samarth, Roshni Karolia, Savitri Sharma, Esther Karunakaran, Lynda Partridge, Sheila MacNeil, Peter N. Monk, Prashant Garg and Sanhita Roy

Microorganisms 2020, 8(2), 260; https://doi.org/10.3390/microorganisms8020260 - 15 Feb 2020

Cited by 18 | Viewed by 3356

Abstract

P. aeruginosa is the most common Gram-negative organism causing bacterial keratitis. Pseudomonas utilizes various virulence mechanisms to adhere and colonize in the host tissue. In the present study, we examined virulence factors associated with thirty-four clinical P. aeruginosa isolates collected from keratitis patients [...] Read more.

P. aeruginosa is the most common Gram-negative organism causing bacterial keratitis. Pseudomonas utilizes various virulence mechanisms to adhere and colonize in the host tissue. In the present study, we examined virulence factors associated with thirty-four clinical P. aeruginosa isolates collected from keratitis patients seeking care at L V Prasad Eye Institute, Hyderabad. The virulence-associated genes in all the isolates were genotyped and characteristics such as antibiotic susceptibility, biofilm formation, swarming motility, pyoverdine production and cell cytotoxicity were analyzed. All the isolates showed the presence of genes related to biofilm formation, alkaline proteases and elastases; however, there was a difference in the presence of genes related to the type III secretion system (T3SS). A higher prevalence of exoU+ genotype was noted in the drug-resistant isolates. All the isolates were capable of forming biofilms and more than 70% of the isolates showed good swarming motility. Pyoverdine production was not associated with the T3SS genotype. In the cytotoxicity assay, the presence of exoS, exoU or both resulted in higher cytotoxicity compared to the absence of both the genes. Overall, our results suggest that the T3SS profile is a good indicator of P. aeruginosa virulence characteristics and the isolates lacking the effector genes may have evolved alternate mechanisms of colonization in the host. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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12 pages, 1860 KiB

Open AccessArticle

CRISPR/Cas9-Mediated Gene Replacement in the Fungal Keratitis Pathogen Fusarium solani var. petroliphilum

by Jorge D. Lightfoot and Kevin K. Fuller

Microorganisms 2019, 7(10), 457; https://doi.org/10.3390/microorganisms7100457 - 16 Oct 2019

Cited by 13 | Viewed by 4055

Abstract

Fungal keratitis (FK) is a site-threatening infection of the cornea associated with ocular trauma and contact lens wear. Members of the Fusarium solani species complex (FSSC) are predominant agents of FK worldwide, but genes that support their corneal virulence are poorly understood. As [...] Read more.

Fungal keratitis (FK) is a site-threatening infection of the cornea associated with ocular trauma and contact lens wear. Members of the Fusarium solani species complex (FSSC) are predominant agents of FK worldwide, but genes that support their corneal virulence are poorly understood. As a means to bolster genetic analysis in FSSC pathogens, we sought to employ a CRISPR/Cas9 system in an FK isolate identified as Fusarium petroliphilum. Briefly, this approach involves the introduction of two components into fungal protoplasts: (1) A purified Cas9 protein complexed with guide RNAs that will direct the ribonuclease to cut on either side of the gene of interest, and (2) a “repair template” comprised of a hygromycin resistance cassette flanked by 40 bp of homology outside of the Cas9 cuts. In this way, Cas9-induced double strand breaks should potentiate double homologous replacement of the repair template at the desired locus. We targeted a putative ura3 ortholog since its deletion would result in an easily discernable uracil auxotrophy. Indeed, 10% of hygromycin-resistant transformants displayed the auxotrophic phenotype, all of which harbored the expected ura3 gene deletion. By contrast, none of the transformants from the repair template control (i.e., no Cas9) displayed the auxotrophic phenotype, indicating that Cas9 cutting was indeed required to promote homologous integration. Taken together, these data demonstrate that the in vitro Cas9 system is an easy and efficient approach for reverse genetics in FSSC organisms, including clinical isolates, which should enhance virulence research in these important but understudied ocular pathogens. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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11 pages, 1111 KiB

Open AccessArticle

Targeted High-Throughput Sequencing Identifies Predominantly Fungal Pathogens in Patients with Clinically Infectious, Culture-Negative Endophthalmitis in South India

by Jaishree Gandhi, Rajagopalaboopathi Jayasudha, Poonam Naik, Savitri Sharma, Vivek Pravin Dave and Joveeta Joseph

Microorganisms 2019, 7(10), 411; https://doi.org/10.3390/microorganisms7100411 - 01 Oct 2019

Cited by 28 | Viewed by 2456

Abstract

To evaluate the clinical utility of high-throughput sequencing (HTS) approach-based analysis of the bacterial and fungal genome in vitreous fluids from patients clinically diagnosed as endophthalmitis, we subjected 75 vitreous fluids from clinically presumed infectious endophthalmitis patients to high-throughput sequencing (Illumina HiSeq 2500) [...] Read more.

To evaluate the clinical utility of high-throughput sequencing (HTS) approach-based analysis of the bacterial and fungal genome in vitreous fluids from patients clinically diagnosed as endophthalmitis, we subjected 75 vitreous fluids from clinically presumed infectious endophthalmitis patients to high-throughput sequencing (Illumina HiSeq 2500) after DNA extraction and amplification of the 16S rRNA for the detection of bacteria, and ITS 2 region for detection of fungal pathogens. As controls, we included vitreous biopsies from 70 patients diagnosed with other non-infectious retinal disorders. Following the construction of the curated microbial genome database and filtering steps to reduce ambiguousness/contaminants from the environment, the paired reads were analyzed. Our HTS reads revealed in almost all cases the same organism that was grown in culture (bacterial-14/15, fungal 3/3) by conventional microbiological workup. HTS additionally diagnosed the presence of microbes in 42/57 (73.7%) patients who were conventionally negative (fungal pathogens in 36/57, bacterial pathogens in 11/57, including five cases that showed the presence of both bacterial and fungal organisms). Aspergillus sp., Fusarium sp., Exserohilum sp., and Candida sp. were the most predominant genera in our cohort of culture-negative endophthalmitis cases. Heat map based microbial clustering analysis revealed that these organisms were taxonomically similar to the species identified by conventional culture methods. Interestingly, 4/70 control samples also showed the presence of bacterial reads, although their clinical significance is uncertain. HTS is useful in detecting pathogens in endophthalmitis cases that elude conventional attempts at diagnosis and can provide actionable information relevant to management, especially where there is a high index of suspicion of fungal endophthalmitis, particularly in tropical countries. Outcome analyses and clinical trials addressing the success and cost savings of HTS for the diagnosis of endophthalmitis are recommended. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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17 pages, 2282 KiB

Open AccessArticle

Molecular Basis of The Retinal Pigment Epithelial Changes That Characterize The Ocular Lesion in Toxoplasmosis

by Shervi Lie, Bárbara R. Vieira, Sigrid Arruda, Milena Simões, Liam M. Ashander, João M. Furtado and Justine R. Smith

Microorganisms 2019, 7(10), 405; https://doi.org/10.3390/microorganisms7100405 - 29 Sep 2019

Cited by 9 | Viewed by 6409

Abstract

When a person becomes infected with Toxoplasma gondii, ocular toxoplasmosis is the most common clinical presentation. The medical literature describes retinitis with surrounding hyperpigmentation secondary to proliferative changes in the retinal pigment epithelium, which is sufficiently characteristic that investigation often is not [...] Read more.

When a person becomes infected with Toxoplasma gondii, ocular toxoplasmosis is the most common clinical presentation. The medical literature describes retinitis with surrounding hyperpigmentation secondary to proliferative changes in the retinal pigment epithelium, which is sufficiently characteristic that investigation often is not needed to make the diagnosis. We aimed to establish the frequency of “typical” ocular toxoplasmosis and delineate its molecular basis. Among 263 patients presenting consecutively with ocular toxoplasmosis to Ribeirão Preto General Hospital in Brazil, where T. gondii infection is endemic, 94.2% of 345 eyes had retinal hyperpigmentation. In ARPE-19 and primary human retinal pigment epithelial cell monolayers exposed to minimal numbers of T. gondii tachyzoites, the proliferation marker–KI-67–was increased in uninfected cells, which also were rendered more susceptible to infection. RT-qPCR and ELISA detected increased expression of vascular endothelial growth factor A (VEGF) and insulin-like growth factor (IGF)1, and decreased expression of thrombospondin (TSP)1 by infected cells. Blockade of VEGF and IGF1—or supplementation of TSP1—reversed the proliferation phenotype in uninfected cells. Our findings confirm that hyperpigmentation is a characteristic feature of retinitis in ocular toxoplasmosis, and demonstrate that T. gondii-infected human retinal pigment epithelial cells secrete VEGF and IGF1, and reduce production of TSP1, to promote proliferation of adjacent uninfected cells and create this disease-specific appearance. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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19 pages, 3846 KiB

Open AccessArticle

Alterations in the Ocular Surface Fungal Microbiome in Fungal Keratitis Patients

by Gumpili Sai Prashanthi, Rajagopalaboopathi Jayasudha, Sama Kalyana Chakravarthy, Shalem Raj Padakandla, Chinthala Reddy SaiAbhilash, Savitri Sharma, Bhupesh Bagga, Somasheila I. Murthy, Prashant Garg and Sisinthy Shivaji

Microorganisms 2019, 7(9), 309; https://doi.org/10.3390/microorganisms7090309 - 02 Sep 2019

Cited by 43 | Viewed by 7887

Abstract

Keratitis, an inflammatory disease of the eye, when neglected could lead to sight-threatening complications and ultimately blindness. Globally, over a million people are affected by keratitis annually. Keratitis has a microbial etiology and is caused by bacteria, fungi, viruses, etc. The present study [...] Read more.

Keratitis, an inflammatory disease of the eye, when neglected could lead to sight-threatening complications and ultimately blindness. Globally, over a million people are affected by keratitis annually. Keratitis has a microbial etiology and is caused by bacteria, fungi, viruses, etc. The present study compared the ocular surface fungal microbiome of healthy individuals and individuals with fungal keratitis. Fungal microbiomes from the conjunctival swabs of healthy individuals and from conjunctival swabs and corneal scrapings of individuals with fungal keratitis were generated using ITS2 region amplicons. Microbiomes were sequenced using Illumina MiSeq 2 × 250 base pair chemistry with a paired-end protocol. Based on Alpha diversity indices, phylum and genera level diversity, abundance differences, and heat map analysis, the fungal microbiomes of conjunctival swabs and corneal scrapings of individuals with fungal keratitis exhibited dysbiosis (alterations in the diversity and abundance) compared to the ocular surface microbiome of the healthy control individuals. This is the first report indicating dysbiosis in the fungal microbiome of conjunctival swabs and corneal scrapings in individuals with fungal keratitis. A total of 11 genera present in the majority of the eyes constituted the variable core ocular microbiome. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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15 pages, 2833 KiB

Open AccessArticle

Pathobiology of Aspergillus Fumigatus Endophthalmitis in Immunocompetent and Immunocompromised Mice

by Neha Gupta, Pawan Kumar Singh, Sanjay G. Revankar, Pranatharthi H. Chandrasekar and Ashok Kumar

Microorganisms 2019, 7(9), 297; https://doi.org/10.3390/microorganisms7090297 - 28 Aug 2019

Cited by 21 | Viewed by 3663

Abstract

Despite Aspergillus being the leading cause of exogenous fungal endophthalmitis following traumatic injury to the eye, its pathogenesis is not fully understood. In the current study, we developed a murine model of Aspergillus fumigatus (AF) endophthalmitis and investigated the disease pathobiology. Endophthalmitis was [...] Read more.

Despite Aspergillus being the leading cause of exogenous fungal endophthalmitis following traumatic injury to the eye, its pathogenesis is not fully understood. In the current study, we developed a murine model of Aspergillus fumigatus (AF) endophthalmitis and investigated the disease pathobiology. Endophthalmitis was induced by intravitreal injection of Aspergillus spores in immunocompetent and immunocompromised (neutropenic) C57BL/6 mice, and disease severity was assessed by eye exam, fungal burden estimation, and histological examination. Our data showed that AF infection caused a time-dependent increase in corneal haze, opacity, and hypopyon beginning at two days post-infection (DPI). The fungal burden in infected eyes of immunocompetent mice peaked at 2 DPI and declined over 9 DPI. AF-infected neuroretina exhibited induction of innate immune response via upregulation of Toll-like receptors (TLRs) and inflammatory mediators (TNFα, IL-1β, and IL6), and increased polymorphonuclear neutrophil (PMN) infiltration. Histological analysis revealed heavy cellular infiltrates in the vitreous cavity as well as disruption of normal retinal architecture and increased retinal cell death. Neutropenic mice exhibited severe disease pathology with the prolonged fungal burden and increased inflammatory mediators. Our study described the first immunocompetent murine model of exogenous AF endophthalmitis and demonstrated an important role of neutrophils in innate defense against fungal endophthalmitis. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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11 pages, 1004 KiB

Open AccessArticle

A Transcriptional Activator of Ascorbic Acid Transport in Streptococcus pneumoniae Is Required for Optimal Growth in Endophthalmitis in a Strain-Dependent Manner

by Angela H. Benton, Mary Darby Jackson, Sandy M. Wong, Justine L. Dees, Brian J. Akerley and Mary E. Marquart

Microorganisms 2019, 7(9), 290; https://doi.org/10.3390/microorganisms7090290 - 24 Aug 2019

Viewed by 2912

Abstract

Streptococcus pneumoniae is among the top causes of bacterial endophthalmitis, an infectious disease of the intraocular fluids. The mechanisms by which S. pneumoniae grows and thrives in the intraocular cavity are not well understood. We used a bacterial genome-wide assessment tool (transposon insertion [...] Read more.

Streptococcus pneumoniae is among the top causes of bacterial endophthalmitis, an infectious disease of the intraocular fluids. The mechanisms by which S. pneumoniae grows and thrives in the intraocular cavity are not well understood. We used a bacterial genome-wide assessment tool (transposon insertion site sequencing) to determine genes essential for S. pneumoniae growth in vitreous humor. The results indicated that an ascorbic acid (AA) transport system subunit was important for growth. We created an isogenic gene deletion mutant of the AA transcriptional activator, ulaR2, in 2 strains of S. pneumoniae. Growth curve analysis indicated that ulaR2 deletion caused attenuated growth in vitro for both strains. However, in vivo vitreous humor infection in rabbits with either strain determined that ulaR2 was necessary for growth in one strain but not the other. These results demonstrate that ulaR2 may be important for fitness during S. pneumoniae endophthalmitis depending on the background of the strain. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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11 pages, 1557 KiB

Open AccessArticle

Anatomic Characterization of the Ocular Surface Microbiome in Children

by Kara M. Cavuoto, Anat Galor and Santanu Banerjee

Microorganisms 2019, 7(8), 259; https://doi.org/10.3390/microorganisms7080259 - 14 Aug 2019

Cited by 20 | Viewed by 3126

Abstract

The microbiome is important in the evolution of the immune system in children; however, information is lacking regarding the composition of the pediatric ocular microbiome and its surrounding structures. A prospective, cross-sectional study of the ocular microbiome was conducted in children <18 years [...] Read more.

The microbiome is important in the evolution of the immune system in children; however, information is lacking regarding the composition of the pediatric ocular microbiome and its surrounding structures. A prospective, cross-sectional study of the ocular microbiome was conducted in children <18 years old. Samples from the inferior conjunctival fornix of both eyes, eyelid margin, and periocular skin underwent DNA amplification and 16S sequencing using Illumina MiSeq 250. The microbiome was analyzed using Qiime. Statistical analysis was performed using a two-sided Student’s t-test, diversity indices, and principal coordinate analysis. A total of 15 children were enrolled. The ocular surface microbiome was predominantly composed of Proteobacteria, whereas Bacteroidetes dominated the eyelid margin, and Firmicutes dominated the periocular skin. Despite these variations, no statistically significant compositional differences were found with Bray-Curtis analysis. The conjunctiva had the lowest Shannon diversity index with a value of 2.3, which was significantly lower than those of the eyelid margin (3.4, p = 0.01) and the periocular skin (3.5, p = 0.001). However, the evenness of the species using Faith’s phylogenetic diversity index was similar at all sites. Overall, the ocular surface microbiome is dominated by Proteobacteria in children. The niche is similar to the surrounding structures in terms of composition, but has a lower number and relative abundance of species. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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13 pages, 1321 KiB

Open AccessArticle

Moraxella nonliquefaciens and M. osloensis Are Important Moraxella Species That Cause Ocular Infections

by Samantha J. LaCroce, Mollie N. Wilson, John E. Romanowski, Jeffrey D. Newman, Vishal Jhanji, Robert M. Q. Shanks and Regis P. Kowalski

Microorganisms 2019, 7(6), 163; https://doi.org/10.3390/microorganisms7060163 - 04 Jun 2019

Cited by 31 | Viewed by 10469

Abstract

Moraxella is an ocular bacterial pathogen isolated in cases of keratitis, conjunctivitis, and endophthalmitis. Gram-negative brick-shaped diplobacilli from ocular specimens, and slow growth in culture, are early indications of Moraxella ocular infection; however, identifying Moraxella to species can be complex and inconsistent. In [...] Read more.

Moraxella is an ocular bacterial pathogen isolated in cases of keratitis, conjunctivitis, and endophthalmitis. Gram-negative brick-shaped diplobacilli from ocular specimens, and slow growth in culture, are early indications of Moraxella ocular infection; however, identifying Moraxella to species can be complex and inconsistent. In this study, bacteria consistent with Moraxella were identified to species using: (1) DNA sequencing coupled with vancomycin susceptibility, (2) MALDI-TOF mass spectrometry, and (3) the Biolog ID system. Study samples consisted of nine ATCC Moraxella controls, 82 isolates from keratitis, 21 isolates from conjunctivitis, and 4 isolates from endophthalmitis. The ATCC controls were correctly identified. For keratitis, 66 (80.5%) were identified as M. nonliquefaciens, 7 (9.0%) as M. lacunata, 5 (6%) as M. osloensis, 2 (2.5%) as Acinetobacter lwoffii, 1 (1.0%) as M. bovis/nonliquefaciens, and 1 (1.0%) as M. osloensis/nonliquefaciens. For conjunctivitis, 9 (43.0%) were identified as M. osloensis, 6 (29.0%) as M. nonliquefaciens, 3 (14.3%) as Roseomonas, 2 (9.5%) as Acinetobacter (parvus, junii), and 1 (4.5%) as M. catarrhalis/nonliquefaciens. From endophthalmitis, 3 of 4 of the isolates were M. nonliquefaciens. Overall, M. nonliquefaciens and M. osloensis were identified in 70% (75 of 107) and 13% (14 of 107) of cases, respectively, totaling 83% (89 of 107). M. nonliquefaciens and M. osloensis are important bacterial pathogens of the eye as determined by DNA sequencing, MALDI-TOF MS, and Biolog. Although Moraxella catarrhalis is a clinical pathogen, other species of Moraxella appear to have a prominent role in eye infections. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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Review

Jump to: Research

10 pages, 557 KiB

Open AccessReview

Pathogenesis of Uveitis in Ebola Virus Disease Survivors: Evolving Understanding from Outbreaks to Animal Models

by Caleb Hartley, J. Clay Bavinger, Sanjana Kuthyar, Jessica G. Shantha and Steven Yeh

Microorganisms 2020, 8(4), 594; https://doi.org/10.3390/microorganisms8040594 - 20 Apr 2020

Cited by 5 | Viewed by 3190

Abstract

Ebola virus disease (EVD) and emerging infectious disease threats continue to threaten life, prosperity and global health security. To properly counteract EVD, an improved understanding of the long-term impact of recent EVD outbreaks in West Africa and the Democratic Republic of Congo are [...] Read more.

Ebola virus disease (EVD) and emerging infectious disease threats continue to threaten life, prosperity and global health security. To properly counteract EVD, an improved understanding of the long-term impact of recent EVD outbreaks in West Africa and the Democratic Republic of Congo are needed. In the wake of recent outbreaks, numerous health sequelae were identified in EVD survivors. These findings include joint pains, headaches, myalgias, and uveitis, a vision-threatening inflammatory condition of the eye. Retrospective and more recent prospective studies of EVD survivors from West Africa have demonstrated that uveitis may occur in 13–34% of patients with an increase in prevalence from baseline to 12-month follow-up. The clinical spectrum of disease ranges from mild, anterior uveitis to severe, sight-threatening panuveitis. Untreated inflammation may ultimately lead to secondary complications of cataract and posterior synechiae, with resultant vision impairment. The identification of Ebola virus persistence in immune privileged organs, such as the eye, with subsequent tissue inflammation and edema may lead to vision loss. Non-human primate models of EVD have demonstrated tissue localization to the eye including macrophage reservoirs within the vitreous matter. Moreover, in vitro models of Ebola virus have shown permissiveness in retinal pigment epithelial cells, potentially contributing to viral persistence. Broad perspectives from epidemiologic studies of the outbreak, animal modeling, and immunologic studies of EVD survivors have demonstrated the spectrum of the eye disease, tissue specificity of Ebola virus infection, and antigen-specific immunologic response. Further studies in these areas will elucidate the mechanisms of this highly prevalent disease with the potential for improved therapeutics for Ebola virus in immune-privileged sites. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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20 pages, 7142 KiB

Open AccessReview

Cytomegalovirus Retinitis in HIV and Non-HIV Individuals

by Monique Munro, Tejabhiram Yadavalli, Cheryl Fonteh, Safa Arfeen and Ann-Marie Lobo-Chan

Microorganisms 2020, 8(1), 55; https://doi.org/10.3390/microorganisms8010055 - 28 Dec 2019

Cited by 56 | Viewed by 7206

Abstract

Cytomegalovirus retinitis (CMVR) is a severe, vision-threatening disease that primarily affects immunosuppressed patients. CMVR is the most common ocular opportunistic infection in human immunodeficiency virus (HIV) infected patients and is the leading cause of blindness in this group; however, the incidence of CMVR [...] Read more.

Cytomegalovirus retinitis (CMVR) is a severe, vision-threatening disease that primarily affects immunosuppressed patients. CMVR is the most common ocular opportunistic infection in human immunodeficiency virus (HIV) infected patients and is the leading cause of blindness in this group; however, the incidence of CMVR in HIV patients has dramatically decreased with antiretroviral therapy. Other causes of immunosuppression, including organ transplantation, hematologic malignancies, and iatrogenic immunosuppression, can also lead to the development of CMVR. Herein, we describe the pathogenesis of CMVR and compare clinical features, epidemiology, and risk factors in HIV and non-HIV infected individuals with CMVR. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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20 pages, 1226 KiB

Open AccessReview

The Best of All Worlds: Streptococcus pneumoniae Conjunctivitis through the Lens of Community Ecology and Microbial Biogeography

by Lawson Ung, Paulo J. M. Bispo, Noelle C. Bryan, Camille Andre, James Chodosh and Michael S. Gilmore

Microorganisms 2020, 8(1), 46; https://doi.org/10.3390/microorganisms8010046 - 25 Dec 2019

Cited by 4 | Viewed by 3244

Abstract

The study of the forces which govern the geographical distributions of life is known as biogeography, a subject which has fascinated zoologists, botanists and ecologists for centuries. Advances in our understanding of community ecology and biogeography—supported by rapid improvements in next generation sequencing [...] Read more.

The study of the forces which govern the geographical distributions of life is known as biogeography, a subject which has fascinated zoologists, botanists and ecologists for centuries. Advances in our understanding of community ecology and biogeography—supported by rapid improvements in next generation sequencing technology—have now made it possible to identify and explain where and why life exists as it does, including within the microbial world. In this review, we highlight how a unified model of microbial biogeography, one which incorporates the classic ecological principles of selection, diversification, dispersion and ecological drift, can be used to explain community dynamics in the settings of both health and disease. These concepts operate on a multiplicity of temporal and spatial scales, and together form a powerful lens through which to study microbial population structures even at the finest anatomical resolutions. When applied specifically to curious strains of conjunctivitis-causing, nonencapsulated Streptococcus pneumoniae, we show how this conceptual framework can be used to explain the possible evolutionary and disease-causing mechanisms which allowed these lineages to colonize and invade a separate biogeography. An intimate knowledge of this radical bifurcation in phylogeny, still the only known niche subspecialization for S. pneumoniae to date, is critical to understanding the pathogenesis of ocular surface infections, nature of host-pathogen interactions, and developing strategies to curb disease transmission. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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17 pages, 1063 KiB

Open AccessReview

Pseudomonas aeruginosa Toxin ExoU as a Therapeutic Target in the Treatment of Bacterial Infections

by Daniel M. Foulkes, Keri McLean, Atikah S. Haneef, David G. Fernig, Craig Winstanley, Neil Berry and Stephen B. Kaye

Microorganisms 2019, 7(12), 707; https://doi.org/10.3390/microorganisms7120707 - 16 Dec 2019

Cited by 32 | Viewed by 6055

Abstract

The opportunistic pathogen Pseudomonas aeruginosa employs the type III secretion system (T3SS) and four effector proteins, ExoS, ExoT, ExoU, and ExoY, to disrupt cellular physiology and subvert the host’s innate immune response. Of the effector proteins delivered by the T3SS, ExoU is the [...] Read more.

The opportunistic pathogen Pseudomonas aeruginosa employs the type III secretion system (T3SS) and four effector proteins, ExoS, ExoT, ExoU, and ExoY, to disrupt cellular physiology and subvert the host’s innate immune response. Of the effector proteins delivered by the T3SS, ExoU is the most toxic. In P. aeruginosa infections, where the ExoU gene is expressed, disease severity is increased with poorer prognoses. This is considered to be due to the rapid and irreversible damage exerted by the phospholipase activity of ExoU, which cannot be halted before conventional antibiotics can successfully eliminate the pathogen. This review will discuss what is currently known about ExoU and explore its potential as a therapeutic target, highlighting some of the small molecule ExoU inhibitors that have been discovered from screening approaches. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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35 pages, 6343 KiB

Open AccessReview

A Pyrrhic Victory: The PMN Response to Ocular Bacterial Infections

by Erin T. Livingston, Md Huzzatul Mursalin and Michelle C. Callegan

Microorganisms 2019, 7(11), 537; https://doi.org/10.3390/microorganisms7110537 - 07 Nov 2019

Cited by 20 | Viewed by 4843

Abstract

Some tissues of the eye are susceptible to damage due to their exposure to the outside environment and inability to regenerate. Immune privilege, although beneficial to the eye in terms of homeostasis and protection, can be harmful when breached or when an aberrant [...] Read more.

Some tissues of the eye are susceptible to damage due to their exposure to the outside environment and inability to regenerate. Immune privilege, although beneficial to the eye in terms of homeostasis and protection, can be harmful when breached or when an aberrant response occurs in the face of challenge. In this review, we highlight the role of the PMN (polymorphonuclear leukocyte) in different bacterial ocular infections that invade the immune privileged eye at the anterior and posterior segments: keratitis, conjunctivitis, uveitis, and endophthalmitis. Interestingly, the PMN response from the host seems to be necessary for pathogen clearance in ocular disease, but the inflammatory response can also be detrimental to vision retention. This “Pyrrhic Victory” scenario is explored in each type of ocular infection, with details on PMN recruitment and response at the site of ocular infection. In addition, we emphasize the differences in PMN responses between each ocular disease and its most common corresponding bacterial pathogen. The in vitro and animal models used to identify PMN responses, such as recruitment, phagocytosis, degranulation, and NETosis, are also outlined in each ocular infection. This detailed study of the ocular acute immune response to infection could provide novel therapeutic strategies for blinding diseases, provide more general information on ocular PMN responses, and reveal areas of bacterial ocular infection research that lack PMN response studies. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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16 pages, 739 KiB

Open AccessReview

Current and Emerging Therapies for Ocular Herpes Simplex Virus Type-1 Infections

by Raghuram Koganti, Tejabhiram Yadavalli and Deepak Shukla

Microorganisms 2019, 7(10), 429; https://doi.org/10.3390/microorganisms7100429 - 10 Oct 2019

Cited by 54 | Viewed by 9973

Abstract

Herpes simplex virus type-1 (HSV-1) is a neurotropic, double-stranded DNA virus that can cause a wide variety of diseases, including many ocular pathologies. It is one of the leading causes of infectious blindness in the United States. Because of its ubiquitous nature and [...] Read more.

Herpes simplex virus type-1 (HSV-1) is a neurotropic, double-stranded DNA virus that can cause a wide variety of diseases, including many ocular pathologies. It is one of the leading causes of infectious blindness in the United States. Because of its ubiquitous nature and its potential to cause serious ocular maladies, there is a significant need for more effective antiviral therapies against ocular HSV-1. In this review, we discuss the lifecycle of HSV-1 as it pertains to corneal infections and the clinically approved as well as emerging treatments to combat HSV-1 infections. We also highlight some newly identified host targets for the antiviral drug development. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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25 pages, 667 KiB

Open AccessReview

MicroRNAs in Ocular Infection

by Shunbin Xu and Linda D. Hazlett

Microorganisms 2019, 7(9), 359; https://doi.org/10.3390/microorganisms7090359 - 17 Sep 2019

Cited by 8 | Viewed by 4265

Abstract

MicroRNAs (miRNAs) are small, non-coding, regulatory RNA molecules and constitute a newly recognized, important layer of gene-expression regulation at post-transcriptional levels. miRNAs quantitatively fine tune the expression of their downstream genes in a cell type- and developmental stage-specific fashion. miRNAs have been proven [...] Read more.

MicroRNAs (miRNAs) are small, non-coding, regulatory RNA molecules and constitute a newly recognized, important layer of gene-expression regulation at post-transcriptional levels. miRNAs quantitatively fine tune the expression of their downstream genes in a cell type- and developmental stage-specific fashion. miRNAs have been proven to play important roles in the normal development and function as well as in the pathogenesis of diseases in all tissues and organ systems. miRNAs have emerged as new therapeutic targets and biomarkers for treatment and diagnosis of various diseases. Although miRNA research in ocular infection remains in its early stages, a handful of pioneering studies have provided insight into the roles of miRNAs in the pathogenesis of parasitic, fungal, bacterial, and viral ocular infections. Here, we review the current status of research in miRNAs in several major ocular infectious diseases. We predict that the field of miRNAs in ocular infection will greatly expand with the discovery of novel miRNA-involved molecular mechanisms that will inform development of new therapies and identify novel diagnostic biomarkers. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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24 pages, 2609 KiB

Open AccessReview

Disparate Entry of Adenoviruses Dictates Differential Innate Immune Responses on the Ocular Surface

by Matthew R. Pennington, Amrita Saha, David F. Painter, Christina Gavazzi, Ashrafali M. Ismail, Xiaohong Zhou, James Chodosh and Jaya Rajaiya

Microorganisms 2019, 7(9), 351; https://doi.org/10.3390/microorganisms7090351 - 13 Sep 2019

Cited by 12 | Viewed by 4732

Abstract

Human adenovirus infection of the ocular surface is associated with severe keratoconjunctivitis and the formation of subepithelial corneal infiltrates, which may persist and impair vision for months to years following infection. Long term pathology persists well beyond the resolution of viral replication, indicating [...] Read more.

Human adenovirus infection of the ocular surface is associated with severe keratoconjunctivitis and the formation of subepithelial corneal infiltrates, which may persist and impair vision for months to years following infection. Long term pathology persists well beyond the resolution of viral replication, indicating that the prolonged immune response is not virus-mediated. However, it is not clear how these responses are sustained or even initiated following infection. This review discusses recent work from our laboratory and others which demonstrates different entry pathways specific to both adenovirus and cell type. These findings suggest that adenoviruses may stimulate specific pattern recognition receptors in an entry/trafficking-dependent manner, leading to distinct immune responses dependent on the virus/cell type combination. Additional work is needed to understand the specific connections between adenoviral entry and the stimulation of innate immune responses by the various cell types present on the ocular surface. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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17 pages, 630 KiB

Open AccessReview

Pseudomonas aeruginosa Keratitis: Protease IV and PASP as Corneal Virulence Mediators

by Richard O’Callaghan, Armando Caballero, Aihua Tang and Michael Bierdeman

Microorganisms 2019, 7(9), 281; https://doi.org/10.3390/microorganisms7090281 - 22 Aug 2019

Cited by 31 | Viewed by 4355

Abstract

Pseudomonas aeruginosa is a leading cause of bacterial keratitis, especially in users of contact lenses. These infections are characterized by extensive degradation of the corneal tissue mediated by Pseudomonas protease activities, including both Pseudomonas protease IV (PIV) and the P. aeruginosa small protease [...] Read more.

Pseudomonas aeruginosa is a leading cause of bacterial keratitis, especially in users of contact lenses. These infections are characterized by extensive degradation of the corneal tissue mediated by Pseudomonas protease activities, including both Pseudomonas protease IV (PIV) and the P. aeruginosa small protease (PASP). The virulence role of PIV was determined by the reduced virulence of a PIV-deficient mutant relative to its parent strain and the mutant after genetic complementation (rescue). Additionally, the non-ocular pathogen Pseudomonas putida acquired corneal virulence when it produced active PIV from a plasmid-borne piv gene. The virulence of PIV is not limited to the mammalian cornea, as evidenced by its destruction of respiratory surfactant proteins and the cytokine interleukin-22 (IL-22), the key inducer of anti-bacterial peptides. Furthermore, PIV contributes to the P. aeruginosa infection of both insects and plants. A possible limitation of PIV is its inefficient digestion of collagens; however, PASP, in addition to cleaving multiple soluble proteins, is able to efficiently cleave collagens. A PASP-deficient mutant lacks the corneal virulence of its parent or rescue strain evidencing its contribution to corneal damage, especially epithelial erosion. Pseudomonas-secreted proteases contribute importantly to infections of the cornea, mammalian lung, insects, and plants. Full article

(This article belongs to the Special Issue Insights Into The Molecular Pathogenesis of Ocular Infections)

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