2023

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37 pages, 1278 KiB

Open AccessReview

Respiratory Syncytial Virus Vaccines: A Review of the Candidates and the Approved Vaccines

by Xanthippi Topalidou, Alexis M. Kalergis and Georgios Papazisis

Pathogens 2023, 12(10), 1259; https://doi.org/10.3390/pathogens12101259 - 19 Oct 2023

Cited by 7 | Viewed by 8303

Respiratory syncytial virus (RSV) is responsible for a significant proportion of global morbidity and mortality affecting young children and older adults. In the aftermath of formalin-inactivated RSV vaccine development, the effort to develop an immunizing agent was carefully guided by epidemiologic and pathophysiological [...] Read more.

Respiratory syncytial virus (RSV) is responsible for a significant proportion of global morbidity and mortality affecting young children and older adults. In the aftermath of formalin-inactivated RSV vaccine development, the effort to develop an immunizing agent was carefully guided by epidemiologic and pathophysiological evidence of the virus, including various vaccine technologies. The pipeline of RSV vaccine development includes messenger ribonucleic acid (mRNA), live-attenuated (LAV), subunit, and recombinant vector-based vaccine candidates targeting different virus proteins. The availability of vaccine candidates of various technologies enables adjustment to the individualized needs of each vulnerable age group. Arexvy^® (GSK), followed by Abrysvo^® (Pfizer), is the first vaccine available for market use as an immunizing agent to prevent lower respiratory tract disease in older adults. Abrysvo is additionally indicated for the passive immunization of infants by maternal administration during pregnancy. This review presents the RSV vaccine pipeline, analyzing the results of clinical trials. The key features of each vaccine technology are also mentioned. Currently, 24 vaccines are in the clinical stage of development, including the 2 licensed vaccines. Research in the field of RSV vaccination, including the pharmacovigilance methods of already approved vaccines, promotes the achievement of successful prevention. Full article

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2022

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2 pages, 175 KiB

Open AccessEditorial

Biomarkers and Pathogenesis of Infectious and Autoimmune Diseases

by Albert A. Rizvanov

Pathogens 2023, 12(1), 14; https://doi.org/10.3390/pathogens12010014 - 22 Dec 2022

Viewed by 970

Abstract

Despite the fact that cardiovascular/ischemic diseases and cancers are major causes of death in the world, infections and autoimmune diseases also carry great burden to healthcare systems [...] Full article

15 pages, 3495 KiB

Open AccessEditor’s ChoiceArticle

SARS-CoV-2 Antibody Effectiveness Is Influenced by Non-Epitope Mutation/Binding-Induced Denaturation of the Epitope 3D Architecture

by Moffat M. Malisheni, Matthew Bates, Albert A. Rizvanov and Paul A. MacAry

Pathogens 2022, 11(12), 1437; https://doi.org/10.3390/pathogens11121437 - 29 Nov 2022

Cited by 2 | Viewed by 1502

Abstract

The public health threat from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to intensify with emerging variants of concern (VOC) aiming to render COVID-19 vaccines/infection-induced antibodies redundant. The SARS-CoV-2 spike protein is responsible for receptor binding and infection of host cells making [...] Read more.

The public health threat from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to intensify with emerging variants of concern (VOC) aiming to render COVID-19 vaccines/infection-induced antibodies redundant. The SARS-CoV-2 spike protein is responsible for receptor binding and infection of host cells making it a legitimate antibody target. Antibodies mostly target epitopes in the receptor binding domain (RBD). Mutations occurring within epitopes influence antibody specificity and function by altering their 3D architecture. However, the mechanisms by which non-epitope mutations in the RBD influence antibody specificity and function remain a mystery. We used Protein Data Bank (PDB) deposited 3D structures for the original, Beta, Delta, BA.1, and BA.2 RBD proteins in complex with either neutralizing antibodies or Angiotensin-Converting Enzyme 2 (ACE2) to elucidate the structural and mechanistic basis for neutralizing antibody evasion driven by non-epitope amino acid substitutions in the RBD. Since the mechanism behind the extensively reported functional discrepancies between the same antibody when used individually and when used in an antibody cocktail is lacking, we explored the structural basis for this inconsistency. Finally, since SARS-CoV-2 antibodies are viral mutagens, we deciphered determinants for antibody-pressured amino acid substitutions. On the one hand, we show that non-epitope mutations in the RBD domain of SARS-CoV-2 VOC influence the formation of hydrogen bonds in the paratope-epitope interface by repositioning RBD amino-acid sidechains (AASCs). This increases the distance between complementary donor/acceptor atoms on paratope and epitope AASCs leading to weaker or the complete prevention of the formation of hydrogen bonds in the paratope-epitope interface. On the other hand, we show that SARS-CoV-2 VOC employ the same strategy to simultaneously search for complementary donor/acceptor atoms on ACE2 AASCs to form new interactions, potentially favoring increased viral transmission. Additionally, we illustrate that converting the spike protein to an RBD, a deletion mutation, also repositions epitope AASCs and that AASC interactions in the paratope-epitope interface vary when an antibody is used individually versus when utilized as a cocktail with other antibodies. Finally, we show that the process of substituting immunogenic RBD amino acids begins with the repositioning of their AASCs induced by immune/antibody pressure. We show that donor/acceptor atoms from any amino acid can determine cross-reactivity instead, provided they possess and present spatially pairing donor/acceptor atoms. By studying structural alignments for PDB deposited antibody-RBD 3D structures and relating them to published binding and neutralization profiles of the same antibodies, we demonstrate that minor structural alterations such as epitope AASC repositioning have a major impact on antibody effectiveness and, hence, should receive adequate attention given that protein structure dictates protein function. Full article

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7 pages, 982 KiB

Open AccessArticle

Increased Levels of C5a in Gingival Crevicular Fluid and Saliva of Patients with Periodontal Disease

by Simran Preet Bhalla, Ann Maria Shaju, Carlos Marcelo da Silva Figueredo and Leticia Algarves Miranda

Pathogens 2022, 11(9), 983; https://doi.org/10.3390/pathogens11090983 - 29 Aug 2022

Cited by 2 | Viewed by 1373

Abstract

C5a is a powerful complement effector molecule that is considered to be an important proinflammatory mediator in several systemic chronic inflammatory diseases. However, its levels in periodontal diseases are yet to be assessed. We aimed to analyse the secretion of C5a in gingival [...] Read more.

C5a is a powerful complement effector molecule that is considered to be an important proinflammatory mediator in several systemic chronic inflammatory diseases. However, its levels in periodontal diseases are yet to be assessed. We aimed to analyse the secretion of C5a in gingival crevicular fluid (GCF) and saliva of patients with periodontal disease. Twenty-eight patients diagnosed with stage 3–4 periodontitis and 16 periodontally healthy subjects participated in this study. GCF was collected from sites with the deepest probing depth of each patient, and volume was measured using a Periotron 8000^®. One mL of unstimulated saliva was also collected. Samples were analysed using a commercially available ELISA kit. The data were analysed using the Mann–Whitney U test, Pearson’s bivariate testing, and receiver operating characteristic curve. C5a was present in GCF from patients with periodontitis (1.06 ± 0.25 ng/mL) whilst it was undetected in controls. Saliva concentration was also significantly higher in periodontitis (1.82 ± 2.31 ng/mL) than controls (0.60 ± 0.72 ng/mL, p = 0.006). C5a levels were more pronounced in periodontitis in both oral fluids assessed by the present pilot study. These results suggest that the more pronounced levels of C5a in oral fluids from periodontitis patients indicate a potential role of this molecule in this disease pathogenesis, deserving to be better explored in subsequent studies. Full article

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2021

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9 pages, 584 KiB

Open AccessReview

Role of Partial Splenectomy in Hematologic Childhood Disorders

by Giorgio Attina’, Silvia Triarico, Alberto Romano, Palma Maurizi, Stefano Mastrangelo and Antonio Ruggiero

Pathogens 2021, 10(11), 1436; https://doi.org/10.3390/pathogens10111436 - 05 Nov 2021

Cited by 8 | Viewed by 5215

Abstract

The spleen is a secondary lymphoid organ that belongs to the reticular-endothelial system, directly connected to blood circulation. The spleen is greatly involved in the immune response, especially against capsulated bacteria. Splenectomy plays a fundamental role in the treatment of numerous pediatric hematologic [...] Read more.

The spleen is a secondary lymphoid organ that belongs to the reticular-endothelial system, directly connected to blood circulation. The spleen is greatly involved in the immune response, especially against capsulated bacteria. Splenectomy plays a fundamental role in the treatment of numerous pediatric hematologic disorders. Taking into account all the possible complications (especially infections) linked to this procedure, alternatives to total splenectomy have been sought. Partial splenectomy has been proposed as a treatment that allows the reduction of infectious risk. This approach has proven safe and feasible in most patients, but multicentric and prospective studies are necessary to more accurately define the indications for performing partial splenectomy. However, vaccinations and antibiotic prophylaxis remain fundamental for preventing serious infections, even in the case of partial splenectomy. We review anatomical and functional properties of the spleen, with a focus on medical or surgical indications to splenectomy, aiming to give practical educational information to patients and their families after splenectomy. Furthermore, we discuss the feasibility of partial splenectomy in children with hematologic diseases who require splenectomy. Full article

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9 pages, 807 KiB

Open AccessCommunication

Epitope-Specific Response of Human Milk Immunoglobulins in COVID-19 Recovered Women

by Tatyana V. Bobik, Nikita N. Kostin, George A. Skryabin, Polina N. Tsabai, Maria A. Simonova, Vera D. Knorre, Yuliana A. Mokrushina, Ivan V. Smirnov, Julia A. Kosolapova, Valentina V. Vtorushina, Evgeniya V. Inviyaeva, Evgeniya Polushkina, Ulyana L. Petrova, Anna V. Levadnaya, Lyubov V. Krechetova, Roman G. Shmakov, Gennadiy T. Sukhikh and Alexander G. Gabibov

Pathogens 2021, 10(6), 705; https://doi.org/10.3390/pathogens10060705 - 05 Jun 2021

Cited by 9 | Viewed by 2781

Abstract

The breastfeeding of infants by mothers who are infected with SARS-CoV-2 has become a dramatic healthcare problem. The WHO recommends that infected women should not abandon breastfeeding; however, there is still the risk of contact transmission. Convalescent donor milk may provide a defense [...] Read more.

The breastfeeding of infants by mothers who are infected with SARS-CoV-2 has become a dramatic healthcare problem. The WHO recommends that infected women should not abandon breastfeeding; however, there is still the risk of contact transmission. Convalescent donor milk may provide a defense against the aforementioned issue and can eliminate the consequences of artificial feeding. Therefore, it is vital to characterize the epitope-specific immunological landscape of human milk from women who recovered from COVID-19. We carried out a comprehensive ELISA-based analysis of blood serum and human milk from maternity patients who had recovered from COVID-19 at different trimesters of pregnancy. It was found that patients predominantly contained SARS-CoV-2 N-protein-specific immunoglobulins and had manifested the antibodies for all the antigens tested in a protein-specific and time-dependent manner. Women who recovered from COVID-19 at trimester I–II showed a noticeable decrease in the number of milk samples with sIgA specific to the N-protein, linear NTD, and RBD-SD1 epitopes, and showed an increase in samples with RBD conformation-dependent sIgA. S-antigens were found to solely induce a sIgA1 response, whereas N-protein sIgA1 and sIgA2 subclasses were involved in 100% and 33% of cases. Overall, the antibody immunological landscape of convalescent donor milk suggests that it may be a potential defense agent against COVID-19 for infants, conferring them with a passive immunity. Full article

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17 pages, 2172 KiB

Open AccessArticle

Cytokine, Chemokine, and Metalloprotease Activation in the Serum of Patients with Nephropathia Epidemica from the Republic of Tatarstan and the Republic of Mordovia, Russia

by Ekaterina Martynova, Yuriy Davidyuk, Emmanuel Kabwe, Ekaterina E. Garanina, Venera Shakirova, Vera Pavelkina, Yulia Uskova, Robert J. Stott, Toshana L. Foster, Maria Markelova, Mehendi Goyal, Abhimat Gupta, Mannan Bhola, Vinay Kumar, Manoj Baranwal, Albert A. Rizvanov and Svetlana F. Khaiboullina

Pathogens 2021, 10(5), 527; https://doi.org/10.3390/pathogens10050527 - 27 Apr 2021

Cited by 10 | Viewed by 2660

Abstract

Nephropathia Epidemica (NE), endemic to several Volga regions of Russia, including the Republic of Tatarstan (RT) and the Republic of Mordovia (RM), is a mild form of hemorrhagic fever with renal syndrome caused by infection with rodent-borne orthohantaviruses. Although NE cases have been [...] Read more.

Nephropathia Epidemica (NE), endemic to several Volga regions of Russia, including the Republic of Tatarstan (RT) and the Republic of Mordovia (RM), is a mild form of hemorrhagic fever with renal syndrome caused by infection with rodent-borne orthohantaviruses. Although NE cases have been reported for decades, little is known about the hantavirus strains associated with human infection in these regions. There is also limited understanding of the pathogenesis of NE in the RT and the RM. To address these knowledge gaps, we conducted comparative analyses of patients with NE in the RT and the RM. Clinical symptoms were more severe in patients with NE from the RM with longer observed duration of fever symptoms and hospitalization. Analysis of patient sera showed changes in the levels of numerous cytokines, chemokines, and matrix metalloproteases (MMPs) in patients with NE from both the RT and the RM, suggesting leukocyte activation, extracellular matrix degradation, and leukocyte chemotaxis. Interestingly, levels of several cytokines were distinctly different between patients NE from the RT when compared with those from the RM. These differences were not related to the genetic variation of orthohantaviruses circulating in those regions, as sequence analysis showed that Puumala virus (PUUV) was the causative agent of NE in these regions. Additionally, only the “Russia” (RUS) genetic lineage of PUUV was detected in the serum samples of patients with NE from both the RT and the RM. We therefore conclude that differences in serum cytokine, chemokine, and MMP levels between the RT and the RM are related to environmental factors and lifestyle differences that influence individual immune responses to orthohantavirus infection. Full article

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16 pages, 1244 KiB

Open AccessArticle

Drift of the Subgingival Periodontal Microbiome during Chronic Periodontitis in Type 2 Diabetes Mellitus Patients

by Irina P. Balmasova, Evgenii I. Olekhnovich, Ksenia M. Klimina, Anna A. Korenkova, Maria T. Vakhitova, Elmar A. Babaev, Leyla A. Ovchinnikova, Yakov A. Lomakin, Ivan V. Smirnov, Victor N. Tsarev, Ashot M. Mkrtumyan, Alexey A. Belogurov, Jr., Alexander G. Gabibov, Elena N. Ilina and Sergey D. Arutyunov

Pathogens 2021, 10(5), 504; https://doi.org/10.3390/pathogens10050504 - 22 Apr 2021

Cited by 16 | Viewed by 2521

Abstract

Since periodontitis and type 2 diabetes mellitus are complex diseases, a thorough understanding of their pathogenesis requires knowing the relationship of these pathologies with other disorders and environmental factors. In this study, the representability of the subgingival periodontal microbiome of 46 subjects was [...] Read more.

Since periodontitis and type 2 diabetes mellitus are complex diseases, a thorough understanding of their pathogenesis requires knowing the relationship of these pathologies with other disorders and environmental factors. In this study, the representability of the subgingival periodontal microbiome of 46 subjects was studied by 16S rRNA gene sequencing and shotgun sequencing of pooled samples. We examined 15 patients with chronic periodontitis (CP), 15 patients with chronic periodontitis associated with type 2 diabetes mellitus (CPT2DM), and 16 healthy subjects (Control). The severity of generalized chronic periodontitis in both periodontitis groups of patients (CP and CPT2DM) was moderate (stage II). The male to female ratios were approximately equal in each group (22 males and 24 females); the average age of the subjects was 53.9 ± 7.3 and 54.3 ± 7.2 years, respectively. The presence of overweight patients (Body Mass Index (BMI) 30–34.9 kg/m²) and patients with class 1–2 obesity (BMI 35–45.9 kg/m²) was significantly higher in the CPT2DM group than in patients having only chronic periodontitis or in the Control group. However, there was no statistically significant difference in all clinical indices between the CP and CPT2DM groups. An analysis of the metagenomic data revealed that the alpha diversity in the CPT2DM group was increased compared to that in the CP and Control groups. The microbiome biomarkers associated with experimental groups were evaluated. In both groups of patients with periodontitis, the relative abundance of Porphyromonadaceae was increased compared to that in the Control group. The CPT2DM group was characterized by a lower relative abundance of Streptococcaceae/Pasteurellaceae and a higher abundance of Leptotrichiaceae compared to those in the CP and Control groups. Furthermore, the CP and CPT2DM groups differed in terms of the relative abundance of Veillonellaceae (which was decreased in the CPT2DM group compared to CP) and Neisseriaceae (which was increased in the CPT2DM group compared to CP). In addition, differences in bacterial content were identified by a combination of shotgun sequencing of pooled samples and genome-resolved metagenomics. The results indicate that there are subgingival microbiome-specific features in patients with chronic periodontitis associated with type 2 diabetes mellitus. Full article

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2020

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14 pages, 905 KiB

Open AccessEditor’s ChoiceReview

Effects of Mycoplasmas on the Host Cell Signaling Pathways

by Sergei N. Borchsenius, Innokentii E. Vishnyakov, Olga A. Chernova, Vladislav M. Chernov and Nikolai A. Barlev

Pathogens 2020, 9(4), 308; https://doi.org/10.3390/pathogens9040308 - 22 Apr 2020

Cited by 15 | Viewed by 5066

Abstract

Mycoplasmas are the smallest free-living organisms. Reduced sizes of their genomes put constraints on the ability of these bacteria to live autonomously and make them highly dependent on the nutrients produced by host cells. Importantly, at the organism level, mycoplasmal infections may cause [...] Read more.

Mycoplasmas are the smallest free-living organisms. Reduced sizes of their genomes put constraints on the ability of these bacteria to live autonomously and make them highly dependent on the nutrients produced by host cells. Importantly, at the organism level, mycoplasmal infections may cause pathological changes to the host, including cancer and severe immunological reactions. At the molecular level, mycoplasmas often activate the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) inflammatory response and concomitantly inhibit the p53-mediated response, which normally triggers the cell cycle and apoptosis. Thus, mycoplasmal infections may be considered as cancer-associated factors. At the same time, mycoplasmas through their membrane lipoproteins (LAMPs) along with lipoprotein derivatives (lipopeptide MALP-2, macrophage-activating lipopeptide-2) are able to modulate anti-inflammatory responses via nuclear translocation and activation of Nrf2 (the nuclear factor-E2-related anti-inflammatory transcription factor 2). Thus, interactions between mycoplasmas and host cells are multifaceted and depend on the cellular context. In this review, we summarize the current information on the role of mycoplasmas in affecting the host’s intracellular signaling mediated by the interactions between transcriptional factors p53, Nrf2, and NF-κB. A better understanding of the mechanisms underlying pathologic processes associated with reprogramming eukaryotic cells that arise during the mycoplasma-host cell interaction should facilitate the development of new therapeutic approaches to treat oncogenic and inflammatory processes. Full article

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22 pages, 6760 KiB

Open AccessArticle

In Vivo Antimicrobial and Wound-Healing Activity of Resveratrol, Dihydroquercetin, and Dihydromyricetin against Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans

by Alexei B. Shevelev, Nicola La Porta, Elena P. Isakova, Stefan Martens, Yulia K. Biryukova, Alexander S. Belous, Dmitrii A. Sivokhin, Elena V. Trubnikova, Marina V. Zylkova, Alla V. Belyakova, Maria S. Smirnova and Yulia I. Deryabina

Pathogens 2020, 9(4), 296; https://doi.org/10.3390/pathogens9040296 - 17 Apr 2020

Cited by 43 | Viewed by 4421

Abstract

An increase in the spread of antibiotic-resistant opportunistic microorganisms causes serious problems in the treatment of purulent infections, burns, and trophic ulcers. We tested the antimicrobial activity in vivo of three polyphenols, Resveratrol, Dihydroquercetin (Taxifolin), and Dihydromyricetin (Ampelopsin) from Norway spruce bark to [...] Read more.

An increase in the spread of antibiotic-resistant opportunistic microorganisms causes serious problems in the treatment of purulent infections, burns, and trophic ulcers. We tested the antimicrobial activity in vivo of three polyphenols, Resveratrol, Dihydroquercetin (Taxifolin), and Dihydromyricetin (Ampelopsin) from Norway spruce bark to promote the elimination of Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans from wounds. Purulent infection was modelled on wounds in rats infected with suspensions containing 10⁹ CFU (colony-forming unit)/mL of pathogens. The wound area was treated daily with solutions of the polyphenols or placebo for 14 days after the beginning of the treatment. The animals were examined daily, and each stage of the wound healing (inflammation, granulation, and maturation (marginal epithelialisation) was documented. The planimetric analysis of the wound recovery percentage was performed on the 3rd, 10th, and 14th day after the start of curing. Then, one echelon (three or four animals from each subgroup) was withdrawn from the experiment on days 3 (three animals), 10 (three animals), and 14 (four animals) for microscopy analysis of cytological composition of their wound defects by microscopy and microbiological analysis of their contamination with pathogens. Our results show that they are also able to suppress mast cell infiltration and stimulate lymphocyte and macrophage (monocyte) infiltration into the wound. Resveratrol stimulated the replacement of the scar with normal tissue (with a clear boundary between the dermis and epidermis) and the restoration of hair follicles. Resveratrol turned out to be significantly better than some commercial antimicrobial (Levomecol) and antifungal (Clotrimazole) ointments and can be proposed as a promising drug for topical use for the treatment of trophic ulcers and burns. Full article

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12 pages, 1496 KiB

Open AccessReview

Inflammasomes as Targets for Adjuvants

by Konstantin Ivanov, Ekaterina Garanina, Albert Rizvanov and Svetlana Khaiboullina

Pathogens 2020, 9(4), 252; https://doi.org/10.3390/pathogens9040252 - 30 Mar 2020

Cited by 21 | Viewed by 3798

Abstract

Inflammasomes are an essential part of the innate immune system. They are necessary for the development of a healthy immune response against infectious diseases. Inflammasome activation leads to the secretion of pro-inflammatory cytokines such as IL-1β and IL-18, which stimulate the adaptive immune [...] Read more.

Inflammasomes are an essential part of the innate immune system. They are necessary for the development of a healthy immune response against infectious diseases. Inflammasome activation leads to the secretion of pro-inflammatory cytokines such as IL-1β and IL-18, which stimulate the adaptive immune system. Inflammasomes activators can be used as adjuvants to provide and maintain the strength of the immune response. This review is focused on the mechanisms of action and the effects of adjuvants on inflammasomes. The therapeutic and prophylaxis significance of inflammasomes in infectious diseases is also discussed. Full article

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8 pages, 883 KiB

Open AccessCase Report

Cerebral HSV-1 Vasculitis as a Fatal Complication of Immunosuppression in Non-Hodgkin´s Lymphoma: A Case Report and Review of the Literature

by Raffaele Nardone, Luca Carnicelli, Francesco Brigo, Slaven Pikija, Larissa Hauer and Johann Sellner

Pathogens 2020, 9(3), 193; https://doi.org/10.3390/pathogens9030193 - 05 Mar 2020

Cited by 2 | Viewed by 2822

Abstract

Patients with lymphoma are predisposed to infection because of the immunocompromised state related to the disease itself and as a consequence of chemo-/radiotherapy. Here, we report a case of Herpes-simplex virus encephalitis (HSE) in an immunosuppressed patient with splenic marginal zone lymphoma (SMZL), [...] Read more.

Patients with lymphoma are predisposed to infection because of the immunocompromised state related to the disease itself and as a consequence of chemo-/radiotherapy. Here, we report a case of Herpes-simplex virus encephalitis (HSE) in an immunosuppressed patient with splenic marginal zone lymphoma (SMZL), a rare indolent variant of non-Hodgkin´s lymphoma (NHL). The course was complicated febrile neutropenia and HSV-1-related cerebral vasculitis causing progressive ischemic stroke. This case illustrates the expanding spectrum of atypical clinical and radiological manifestations of HSE in patients treated with myelotoxic drugs. Moreover, we summarize the few central nervous system manifestations of SMZL reported in the literature and discuss distinct causes of neurological deterioration in patients with NHL. Full article

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