Viruses

26 pages, 9055 KiB

Open AccessArticle

Phylogenomic Signatures of a Lineage of Vesicular Stomatitis Indiana Virus Circulating During the 2019–2020 Epidemic in the United States

by Selene Zarate, Miranda Bertram, Case Rodgers, Kirsten Reed, Angela Pelzel-McCluskey, Ninnet Gomez-Romero, Luis L. Rodriguez, Christie Mayo, Chad Mire, Sergei L. Kosakovsky Pond and Lauro Velazquez-Salinas

Viruses 2024, 16(11), 1803; https://doi.org/10.3390/v16111803 - 20 Nov 2024

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Abstract

For the first time, we describe phylogenomic signatures of an epidemic lineage of vesicular stomatitis Indiana virus (VSIV). We applied multiple evolutionary analyses to a dataset of 87 full-length genome sequences representing the circulation of an epidemic VSIV lineage in the US between [...] Read more.

For the first time, we describe phylogenomic signatures of an epidemic lineage of vesicular stomatitis Indiana virus (VSIV). We applied multiple evolutionary analyses to a dataset of 87 full-length genome sequences representing the circulation of an epidemic VSIV lineage in the US between 2019 and 2020. Based on phylogenetic analyses, we predicted the ancestral relationship of this lineage with a specific group of isolates circulating in the endemic zone of Chiapas, Mexico. Subsequently, our findings indicate that the lineage diversified into at least four different subpopulations during its circulation in the US. We identified single nucleotide polymorphisms (SNPs) that differentiate viral subpopulations and assessed their potential relevance using comparative phylogenetic methods, highlighting the preponderance of synonymous mutations during the differentiation of these populations. Purifying selection was the main evolutionary force favoring the conservation of this epidemic phenotype, with P and G genes as the main drivers of the evolution of this lineage. Our analyses identified multiple codon sites under positive selection and the association of these sites with specific functional domains at P, M, G, and L proteins. Based on ancestral reconstruction analyses, we showed the potential relevance of some of the sites identified under positive selection to the adaptation of the epidemic lineage at the population level. Finally, using a representative group of viruses from Colorado, we established a positive correlation between genetic and geographical distances, suggesting that positive selection on specific codon positions might have favored the adaptation of different subpopulations to circulation in specific geographical settings. Collectively, our study reveals the complex dynamics that accompany the evolution of an epidemic lineage of VSIV in nature. Our analytical framework provides a model for conducting future evolutionary analyses. The ultimate goal is to support the implementation of an early warning system for vesicular stomatitis virus in the US, enabling early detection of epidemic precursors from Mexico. Full article

(This article belongs to the Section Animal Viruses)

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14 pages, 2348 KiB

Open AccessArticle

Chimeric Virus-like Particles of Physalis Mottle Virus as Carriers of M2e Peptides of Influenza a Virus

by Elena A. Blokhina, Eugenia S. Mardanova, Anna A. Zykova, Marina A. Shuklina, Liudmila A. Stepanova, Liudmila M. Tsybalova and Nikolai V. Ravin

Viruses 2024, 16(11), 1802; https://doi.org/10.3390/v16111802 - 20 Nov 2024

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Abstract

Plant viruses and virus-like particles (VLPs) are safe for mammals and can be used as a carrier/platform for the presentation of foreign antigens in vaccine development. The aim of this study was to use the coat protein (CP) of Physalis mottle virus (PhMV) [...] Read more.

Plant viruses and virus-like particles (VLPs) are safe for mammals and can be used as a carrier/platform for the presentation of foreign antigens in vaccine development. The aim of this study was to use the coat protein (CP) of Physalis mottle virus (PhMV) as a carrier to display the extracellular domain of the transmembrane protein M2 of influenza A virus (M2e). M2e is a highly conserved antigen, but to induce an effective immune response it must be linked to an adjuvant or carrier VLP. Four tandem copies of M2e were either fused to the N-terminus of the full-length PhMV CP or replaced the 43 N-terminal amino acids of the PhMV CP. Only the first fusion protein was successfully expressed in Escherichia coli, where it self-assembled into spherical VLPs of about 30 nm in size. The particles were efficiently recognized by anti-M2e antibodies, indicating that the M2e peptides were exposed on the surface. Subcutaneous immunization of mice with VLPs carrying four copies of M2e induced high levels of M2e-specific IgG antibodies in serum and protected animals from a lethal influenza A virus challenge. Therefore, PhMV particles carrying M2e peptides may become useful research tools for the development of recombinant influenza vaccines. Full article

(This article belongs to the Special Issue Nanovaccines against Viral Infection)

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13 pages, 2808 KiB

Open AccessArticle

Investigation of Polymorphisms Induced by the Solo Long Terminal Repeats (Solo-LTRs) in Porcine Endogenous Retroviruses (ERVs)

by Cai Chen, Zhanyu Du, Yao Zheng, Hong Chen, Ahmed A. Saleh, Naisu Yang, Mengli Wang, Phiri Azele, Xiaoyan Wang and Chengyi Song

Viruses 2024, 16(11), 1801; https://doi.org/10.3390/v16111801 - 20 Nov 2024

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Abstract

Homologous recombination events take place between the 5′ and 3′ long terminal repeats (LTRs) of ERVs, resulting in the generation of solo-LTR, which can cause solo-LTR-associated polymorphism across different genomes. In the current study, specific criteria were established for the filtration of solo-LTRs, [...] Read more.

Homologous recombination events take place between the 5′ and 3′ long terminal repeats (LTRs) of ERVs, resulting in the generation of solo-LTR, which can cause solo-LTR-associated polymorphism across different genomes. In the current study, specific criteria were established for the filtration of solo-LTRs, resulting in an average of 5630 solo-LTRs being identified in 21 genomes. Subsequently, a protocol was developed for detecting solo-LTR polymorphisms in the pig genomes, resulting in the discovery of 927 predicted solo-LTR polymorphic sites. Following verification and filtration processes, 603 highly reliable solo-LTR polymorphic sites were retained, involving 446 solo-LTR presence sites (solo-LTR⁺) and 157 solo-LTR absence sites (solo-LTR⁻) relative to the reference genome. Intersection analysis with gene/functional regions revealed that 248 solo-LTR⁻ sites and 23 solo-LTR⁺ sites overlapped with genes or were in the vicinity of genes or functional regions, impacting a diverse range of gene structures. Moreover, through the utilization of 156 solo-LTR polymorphic sites for population genetic analysis, it was observed that these solo-LTR loci effectively clustered various breeds together, aligning with expectations and underscoring their practical utility. This study successfully established a methodology for detecting solo-LTR polymorphic sites. By applying these methods, a total of 603 high-reliability solo-LTR polymorphic sites were pinpointed, with nearly half of them being linked to genes or functional regions. Full article

(This article belongs to the Section Animal Viruses)

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13 pages, 1160 KiB

Open AccessArticle

Assessment of Bacteriophage Pharmacokinetic Parameters After Intra-Articular Delivery in a Rat Prosthetic Joint Infection Model

by Jason Young, Mohammad Javad Shariyate, Prateek Misra, Shubham Laiwala, Ara Nazarian and Edward Kenneth Rodriguez

Viruses 2024, 16(11), 1800; https://doi.org/10.3390/v16111800 - 20 Nov 2024

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Abstract

Prosthetic joint infections (PJIs) are a serious complication of orthopedic surgery. Bacteriophage (phage) therapy shows promise as an adjunctive treatment but requires further study, particularly in its pharmacokinetics. Consequently, we performed a pharmacokinetic assessment of phage therapy for PJIs using a Staphylococcus epidermidis [...] Read more.

Prosthetic joint infections (PJIs) are a serious complication of orthopedic surgery. Bacteriophage (phage) therapy shows promise as an adjunctive treatment but requires further study, particularly in its pharmacokinetics. Consequently, we performed a pharmacokinetic assessment of phage therapy for PJIs using a Staphylococcus epidermidis Kirschner wire-based prosthesis rat model. We used 52 male Sprague–Dawley rats in four groups: negative controls (no phage, sterile implant), PJI controls (bacteria, no phage), sterile phage (phages given, sterile implant), and PJI (bacteria, phages given). The PJI groups were inoculated with ~10⁶ CFU of S. epidermidis. The groups receiving phage were intra-articularly injected with ~10⁸ PFU of vB_SepM_Alex five days post-implantation. The rats were euthanized between 30 min and 48 h post-injection. The measured phage concentrations between the PJI rats and the sterile controls in periarticular tissues were not significantly different. In a noncompartmental pharmacokinetic analysis, the estimated phage half-lives were under 6 h (combined: 3.73 [IQR, 1.45, 10.07]). The maximum phage concentrations were reached within 2 h after administration (combined: 0.75 [0.50, 1.75]). The estimated phage mean residence time was approximately three hours (combined: 3.04 [1.44, 4.19]). Our study provides a preliminary set of pharmacokinetic parameters that can inform future phage dosing studies and animal models of phage therapy for PJIs. Full article

(This article belongs to the Special Issue Phage-Bacteria Interplay in Health and Disease, Second Edition)

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14 pages, 1326 KiB

Open AccessArticle

The Predictive Role of miRNAs in Hepatitis B Vaccine Response of Metabolic Dysfunction-Associated Steatotic Liver Disease Patients

by Gamze Guney Eskiler, Oguz Karabay, Mukaddes Tozlu, Ayhan Aydin, Kaan Furkan Hamarat, Umut Alkurt, Asuman Deveci Ozkan and Yasemin Gunduz

Viruses 2024, 16(11), 1799; https://doi.org/10.3390/v16111799 - 20 Nov 2024

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Abstract

(1) Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease. Although the changes in the expression levels of microRNAs (miRNAs) in hepatitis B virus-related diseases have been evaluated, no study has evaluated the role of miRNAs in HBV [...] Read more.

(1) Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease. Although the changes in the expression levels of microRNAs (miRNAs) in hepatitis B virus-related diseases have been evaluated, no study has evaluated the role of miRNAs in HBV vaccine response in MASLD patients. We aimed to determine the miRNA expression profile in MASLD patients according to HBV vaccine response. (2) Methods: Overall, 100 MASLD patients and 100 controls were included, and anti-HBs levels were measured after three doses of HBV vaccine administration. After collecting blood samples, 22 different miRNA expression profiles were analyzed by RT-PCR analysis, and changes in the expression levels of potential miRNAs were further verified in all study groups. (3) Results: The miR-146a expression level considerably increased in MASLD patients compared to the control group. Furthermore, miR-99a and miR-640 expression levels significantly increased in AntiHBs (−) healthy individuals. (4): Conclusions: miR-146a could be used as the diagnostic marker in MASLD patients. Furthermore, the miR-99a and miR-640 expression levels could predict hepatitis B vaccine response. However, validation studies are required to verify the biomarker potential of miRNAs within a more significant number of patients. Full article

(This article belongs to the Section Human Virology and Viral Diseases)

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23 pages, 3398 KiB

Open AccessArticle

Unveiling the Role of TMPRSS2 in the Proteolytic Activation of Pandemic and Zoonotic Influenza Viruses and Coronaviruses in Human Airway Cells

by Marie Schwerdtner, Luna C. Schmacke, Julia Nave, Hannah Limburg, Torsten Steinmetzer, David A. Stein, Hong M. Moulton and Eva Böttcher-Friebertshäuser

Viruses 2024, 16(11), 1798; https://doi.org/10.3390/v16111798 - 20 Nov 2024

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Abstract

The zoonotic transmission of influenza A viruses (IAVs) and coronaviruses (CoVs) may result in severe disease. Cleavage of the surface glycoproteins hemagglutinin (HA) and spike protein (S), respectively, is essential for viral infectivity. The transmembrane serine protease 2 (TMPRSS2) is crucial for cleaving [...] Read more.

The zoonotic transmission of influenza A viruses (IAVs) and coronaviruses (CoVs) may result in severe disease. Cleavage of the surface glycoproteins hemagglutinin (HA) and spike protein (S), respectively, is essential for viral infectivity. The transmembrane serine protease 2 (TMPRSS2) is crucial for cleaving IAV HAs containing monobasic cleavage sites and severe acute respiratory syndrome (SARS)-CoV-2 S in human airway cells. Here, we analysed and compared the TMPRSS2-dependency of SARS-CoV, Middle East respiratory syndrome (MERS)-CoV, the 1918 pandemic H1N1 IAV and IAV H12, H13 and H17 subtypes in human airway cells. We used the peptide-conjugated morpholino oligomer (PPMO) T-ex5 to knockdown the expression of active TMPRSS2 and determine the impact on virus activation and replication in Calu-3 cells. The activation of H1N1/1918 and H13 relied on TMPRSS2, whereas recombinant IAVs carrying H12 or H17 were not affected by TMPRSS2 knockdown. MERS-CoV replication was strongly suppressed in T-ex5 treated cells, while SARS-CoV was less dependent on TMPRSS2. Our data underline the importance of TMPRSS2 for certain (potentially) pandemic respiratory viruses, including H1N1/1918 and MERS-CoV, in human airways, further suggesting a promising drug target. However, our findings also highlight that IAVs and CoVs differ in TMPRSS2 dependency and that other proteases are involved in virus activation. Full article

(This article belongs to the Special Issue TMPRSS2 in Influenza Virus and Coronavirus Infections)

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20 pages, 7161 KiB

Open AccessArticle

Single-Cell Transcriptomics of Human Tonsils Reveals Nicotine Enhances HIV-1-Induced NLRP3 Inflammasome and Mitochondrial Activation

by Nadine Schrode, Trinisia Fortune, Aislinn M. Keane, Jesse F. Mangold, Benjamin Tweel, Kristin G. Beaumont and Talia H. Swartz

Viruses 2024, 16(11), 1797; https://doi.org/10.3390/v16111797 - 20 Nov 2024

Viewed by 402

Abstract

Background: HIV-1 infection, even with effective antiretroviral therapy (ART), is associated with chronic inflammation and immune dysfunction, contributing to long-term health complications. Nicotine use, prevalent among people with HIV (PWH), is known to exacerbate immune activation and disease progression, but the precise biological [...] Read more.

Background: HIV-1 infection, even with effective antiretroviral therapy (ART), is associated with chronic inflammation and immune dysfunction, contributing to long-term health complications. Nicotine use, prevalent among people with HIV (PWH), is known to exacerbate immune activation and disease progression, but the precise biological mechanisms remain to be fully understood. This study sought to uncover the synergistic effects of HIV-1 infection and nicotine on immune cell function, focusing on beneficial insights into NLRP3 inflammasome activation, oxidative stress, and mitochondrial pathways. Methods: Human tonsil explants were infected with HIV-1 and exposed to nicotine. Single-cell RNA sequencing was used to profile immune cell populations and gene expression linked to inflammasome activation, oxidative stress, and mitochondrial function. Gene set enrichment analysis (GSEA) and synergy assessments were conducted to investigate how nicotine modulates immune responses in the context of HIV. Results: The combination of HIV infection and nicotine exposure significantly increased NLRP3 inflammasome activation, thioredoxin, and components of oxidative phosphorylation. Conclusions: This study highlights how the combined effects of HIV-1 and nicotine offer valuable insights into immune modulation, opening doors for future therapeutic strategies. Targeting the NLRP3 inflammasome and addressing nicotine use may contribute to improved outcomes for PWH. Full article

(This article belongs to the Special Issue HIV-1 Infection and Immunometabolism: Relevance to HIV Pathogenesis and Persistence 3.0)

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13 pages, 1736 KiB

Open AccessArticle

Reexamination of the Sida Micrantha Mosaic Virus and Sida Mottle Virus Complexes: Classification Status, Diversity, Cognate DNA–B Components, and Host Spectrum

by Marcos Silva de Queiroz-Ferreira, Luciane de Nazaré Almeida dos Reis, Maria Esther de Noronha Fonseca, Felipe Fochat Silva Melo, Ailton Reis, Leonardo Silva Boiteux and Rita de Cássia Pereira-Carvalho

Viruses 2024, 16(11), 1796; https://doi.org/10.3390/v16111796 - 19 Nov 2024

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Abstract

Sida mottle virus (SiMoV) and Sida micrantha mosaic virus (SiMMV) are major Brazilian begomoviruses (Geminiviridae). However, the range of DNA–A identity of isolates of these viruses (81–100%) is not in agreement with the current criteria for Begomovirus species demarcation (<91%). To [...] Read more.

Sida mottle virus (SiMoV) and Sida micrantha mosaic virus (SiMMV) are major Brazilian begomoviruses (Geminiviridae). However, the range of DNA–A identity of isolates of these viruses (81–100%) is not in agreement with the current criteria for Begomovirus species demarcation (<91%). To clarify this putative classification problem, we performed a comprehensive set of molecular analyses with all 53 publicly available isolates (with complete DNA–A genomes) designated as either SiMoV or SiMMV (including novel isolates obtained herein from nationwide metagenomics-based studies). Two well-defined phylogenetic clusters were identified. The SiMMV complex (n = 47) comprises a wide range of strains (with a continuum variation of 88.8–100% identity) infecting members of five botanical families (Malvaceae, Solanaceae, Fabaceae, Oxalidaceae, and Passifloraceae). The SiMoV group now comprises eight isolates (90–100% identity) restricted to Malvaceae hosts, including one former reference SiMMV isolate (gb|NC_077711) and SP77 (gb|FN557522; erroneously named as “true SiMMV”). Iteron analyses of metagenomics-derived information allowed for the discovery of the missing DNA–B cognate of SiMoV (93.5% intergenic region identity), confirming its bipartite nature. Henceforth, the correct identification of SiMoV and SiMMV isolates will be a crucial element for effective classical and biotech resistance breeding of the viral host species. Full article

(This article belongs to the Section Viruses of Plants, Fungi and Protozoa)

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19 pages, 779 KiB

Open AccessReview

Beyond Antivirals: Alternative Therapies for Long COVID

by Achilleas Livieratos, Charalambos Gogos and Karolina Akinosoglou

Viruses 2024, 16(11), 1795; https://doi.org/10.3390/v16111795 - 19 Nov 2024

Viewed by 315

Abstract

Long COVID or Post-Acute Sequelae of SARS-CoV-2 infection (PASC) is a condition characterized by numerous lingering symptoms that persist for weeks to months following the viral illness. While treatment for PASC is still evolving, several therapeutic approaches beyond traditional antiviral therapies are being [...] Read more.

Long COVID or Post-Acute Sequelae of SARS-CoV-2 infection (PASC) is a condition characterized by numerous lingering symptoms that persist for weeks to months following the viral illness. While treatment for PASC is still evolving, several therapeutic approaches beyond traditional antiviral therapies are being investigated, such as immune-modulating agents, anti-inflammatory drugs, and various supportive interventions focusing at alleviating symptoms and enhancing recovery. We aimed to summarize the breadth of available evidence, identify knowledge gaps, and highlight promising non-antiviral therapies for Long COVID/PASC. We followed the framework of a scoping methodology by mapping existing evidence from a range of studies, including randomized clinical trials, observational research, and case series. Treatments evaluated include metformin, low-dose naltrexone (LDN), dexamethasone, statins, omega-3 fatty acids, L-arginine, and emerging therapies like intravenous immunoglobulin (IVIg) and therapeutic apheresis. Early findings suggest that metformin has the strongest clinical evidence, particularly from large phase 3 trials, while LDN and dexamethasone show potential based on observational studies. However, many treatments lack robust, large-scale trials. This review emphasizes the need for further research to confirm the efficacy of these treatments and guide clinical practice for Long COVID management. Full article

(This article belongs to the Special Issue Women in Virology 2024)

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17 pages, 951 KiB

Open AccessReview

Rapid Development of Small Rodent Animal Models for Infectious Disease Research Through Vectorized Receptor Molecule Expression

by Melanie M. Goens, Erin L. Howard, Bryce M. Warner, Leonardo Susta and Sarah K. Wootton

Viruses 2024, 16(11), 1794; https://doi.org/10.3390/v16111794 - 19 Nov 2024

Viewed by 451

Abstract

The emergence and re-emergence of pathogens with pandemic potential has been a persistent issue throughout history. Recent decades have seen significant outbreaks of zoonotic viruses from members of the Coronaviridae, Filoviridae, Paramyxoviridae, Flaviviridae, and Togaviridae families, resulting in widespread [...] Read more.

The emergence and re-emergence of pathogens with pandemic potential has been a persistent issue throughout history. Recent decades have seen significant outbreaks of zoonotic viruses from members of the Coronaviridae, Filoviridae, Paramyxoviridae, Flaviviridae, and Togaviridae families, resulting in widespread infections. The continual emergence of zoonotic viral pathogens and associated infections highlights the need for prevention strategies and effective treatments. Central to this effort is the availability of suitable animal models, which are essential for understanding pathogenesis and assessing transmission dynamics. These animals are also critical for evaluating the safety and efficacy of novel vaccines or therapeutics and are essential in facilitating regulatory approval of new products. Rapid development of animal models is an integral aspect of pandemic response and preparedness; however, their establishment is fraught by several rate-limiting steps, including selection of a suitable species, the logistical challenges associated with sharing and disseminating transgenic animals (e.g., the time-intensive nature of breeding and maintaining colonies), the availability of technical expertise, as well as ethical and regulatory approvals. A method for the rapid development of relevant animal models that has recently gained traction, in large part due to the COVID-19 pandemic, is the use of gene therapy vectors to express human viral receptors in readily accessible laboratory animals to enable virus infection and development of clinical disease. These models can be developed rapidly on any genetic background, making mechanistic studies and accelerated evaluation of novel countermeasures possible. In this review, we will discuss important considerations for the effective development of animal models using viral vector approaches and review the current vector-based animal models for studying viral pathogenesis and evaluating prophylactic and therapeutic strategies, with an emphasis on models of SARS-CoV-2 infection based on the vectorized expression of human angiotensin-converting enzyme 2. Full article

(This article belongs to the Special Issue Animal Models for Virology Research)

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2 pages, 141 KiB

Open AccessEditorial

Understanding and Targeting HBV Transcription and Post-Transcriptional Regulation

by Simon P. Fletcher and Rudolf K. Beran

Viruses 2024, 16(11), 1793; https://doi.org/10.3390/v16111793 - 19 Nov 2024

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Abstract

Chronic hepatitis B (CHB) affects approximately 300 million people worldwide and current therapies rarely cure it [...] Full article

(This article belongs to the Special Issue HBV Transcriptional and Post-transcriptional Regulation)

20 pages, 1131 KiB

Open AccessReview

Elimination of HCV Infection: Recent Epidemiological Findings, Barriers, and Strategies for the Coming Years

by Pietro Torre, Mariano Festa, Tommaso Sarcina, Mario Masarone and Marcello Persico

Viruses 2024, 16(11), 1792; https://doi.org/10.3390/v16111792 - 19 Nov 2024

Viewed by 551

Abstract

Hepatitis C is a disease for which in approximately 30 years we have gone from the discovery of the causative agent in 1989, to the introduction of direct-acting antiviral (DAAs) therapies starting from 2011, and to a proposal for its elimination in 2016, [...] Read more.

Hepatitis C is a disease for which in approximately 30 years we have gone from the discovery of the causative agent in 1989, to the introduction of direct-acting antiviral (DAAs) therapies starting from 2011, and to a proposal for its elimination in 2016, with some countries being on track for this goal. Elimination efforts, in the absence of a vaccine, rely on prevention measures and antiviral therapies. However, treatment rates have declined in recent years and are not considered adequate to achieve this goal at a global level. This poses a great epidemiological challenge, as HCV in many countries still causes a significant burden and most infected people are not yet diagnosed. Consequently, efforts are needed at different levels with common purposes: to facilitate access to screening and diagnosis and to improve linkage to care pathways. In this review, we discuss the latest epidemiological findings on HCV infection, the obstacles to its elimination, and strategies that are believed to be useful to overcome these obstacles but are applied unevenly across the world. Full article

(This article belongs to the Special Issue Hepatitis C Virus: From Epidemiology to Treatment)

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2 pages, 153 KiB

Open AccessEditorial

SARS-CoV-2 Neutralizing Antibodies 2.0

by Youchun Wang

Viruses 2024, 16(11), 1791; https://doi.org/10.3390/v16111791 - 19 Nov 2024

Viewed by 305

Abstract

As the SARS-CoV-2 mutates, especially into those variants causing immune escape, COVID-19 continues to wreak havoc [...] Full article

(This article belongs to the Special Issue SARS-CoV-2 Neutralizing Antibodies 2.0)

17 pages, 1871 KiB

Open AccessReview

Breaching the Barrier: Investigating Initial Herpes Simplex Viral Infection and Spread in Human Skin and Mucosa

by Hafsa Rana, Naomi R. Truong, Dona R. Sirimanne and Anthony L. Cunningham

Viruses 2024, 16(11), 1790; https://doi.org/10.3390/v16111790 - 18 Nov 2024

Viewed by 407

Abstract

Herpes simplex virus (HSV) is sexually transmitted via the anogenital mucosa where it initially infects epidermal keratinocytes and mononuclear phagocytes (MNPs). It then spreads to the dorsal root ganglion via sensory nerve endings, to remain latent for life with periodic reactivation. Currently, there [...] Read more.

Herpes simplex virus (HSV) is sexually transmitted via the anogenital mucosa where it initially infects epidermal keratinocytes and mononuclear phagocytes (MNPs). It then spreads to the dorsal root ganglion via sensory nerve endings, to remain latent for life with periodic reactivation. Currently, there is no cure or vaccine. Initial or recurrent HSV infection can produce serious complications and mediate acquisition of HIV. This review outlines the initial events after the HSV infection of human anogenital mucosa to determine the optimal window to target the virus before it becomes latent. After infection, HSV spreads rapidly within the mid-layers of epidermal keratinocytes in the explanted human inner foreskin. Infected cells produce chemokines, which modulate nectin-1 distribution on the surface of adjacent keratinocytes, facilitating viral spread. Epidermal Langerhans cells and dendritic cells become infected with HSV followed by a “viral relay” to dermal MNPs, which then present viral antigen to T cells in the dermis or lymph nodes. These data indicate the need for interruption of spread within 24 h by diffusible vaccine-induced mediators such as antiviral cytokines from resident immune cells or antibodies. Intradermal/mucosal vaccines would need to target the relevant dermal MNPs to induce HSV-specific CD4⁺ and CD8⁺ T cells. Full article

(This article belongs to the Special Issue Innate and Adaptive Immunity to Cutaneous Virus Infection)

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10 pages, 240 KiB

Open AccessArticle

Interest and Expectations for a Herpes Vaccine Among People Diagnosed with Genital HSV 1-2 Infection: Results from an Italian Survey

by Lovel Lisac, Angelo Roberto Raccagni, Riccardo Lolatto, Flavia Passini, Chiara Maci, Elena Bruzzesi, Nicolò Moschetta, Antonella Castagna and Silvia Nozza

Viruses 2024, 16(11), 1789; https://doi.org/10.3390/v16111789 - 18 Nov 2024

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Abstract

Genital herpes simplex virus (HSV) is associated with a reduction in quality of life and adverse outcomes. The aim of this study is to assess the interest and expectations for a therapeutic HSV vaccine among individuals diagnosed with genital herpes in Italy. A [...] Read more.

Genital herpes simplex virus (HSV) is associated with a reduction in quality of life and adverse outcomes. The aim of this study is to assess the interest and expectations for a therapeutic HSV vaccine among individuals diagnosed with genital herpes in Italy. A retrospective survey was conducted at the Infectious Diseases Unit of the IRCCS San Raffaele Scientific Institute, Milan, Italy. The study collected data on demographics, clinical history and interest in HSV vaccination. The results showed that 87.5% of participants were interested in a therapeutic vaccine, with interest higher among younger people and those with frequent genital herpes recurrences. Participants most expected the vaccine to reduce the pain associated with outbreaks, followed by a reduction in the frequency and duration of recurrences. These findings underscore the strong demand for a therapeutic HSV vaccine, especially among those who experience recurrent outbreaks, and highlight the importance of considering patient expectations when developing preventive and therapeutic strategies for genital herpes. Full article

(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)

3 pages, 149 KiB

Open AccessEditorial

Special Issue: Research on Herpes Virus Fusion and Entry

by Doina Atanasiu and Tina M. Cairns

Viruses 2024, 16(11), 1788; https://doi.org/10.3390/v16111788 - 18 Nov 2024

Viewed by 317

Abstract

Herpesviridae comprise a large family of enveloped DNA viruses with a unifying ability to establish a latent infection in their host [...] Full article

(This article belongs to the Special Issue Research on Herpes Virus Fusion and Entry)

19 pages, 15576 KiB

Open AccessArticle

IPEC-J2 Autophagy Induced by TLR4 and NSP6 Interactions Facilitate Porcine Epidemic Diarrhea Virus Replication

by Haiyuan Zhao, Dianzhong Zheng, Qinyuan Chang, Hailin Zhang, Yilan Shao, Jiaxuan Li, Wen Cui, Yanping Jiang, Lijie Tang, Yijing Li and Xiaona Wang

Viruses 2024, 16(11), 1787; https://doi.org/10.3390/v16111787 - 17 Nov 2024

Viewed by 541

Abstract

Autophagy is an important cellular response against intracellular pathogens. However, some viruses have evolved mechanisms to hijack this defensive process to provide favorable conditions for virus replication in host cells. The porcine epidemic diarrhea virus (PEDV) has been shown to alter autophagy pathways; [...] Read more.

Autophagy is an important cellular response against intracellular pathogens. However, some viruses have evolved mechanisms to hijack this defensive process to provide favorable conditions for virus replication in host cells. The porcine epidemic diarrhea virus (PEDV) has been shown to alter autophagy pathways; however, it is still unknown through which receptors PEDV induces autophagy in IPEC-J2 cells, whether autophagy facilitates PEDV replication, and which functional domains of PEDV proteins are primarily responsible for inducing autophagy. Here, we found that PEDV infection induces autophagy in host cells via distinct and uncoupled molecular pathways. RNA-seq technology was used to analyze the expression patterns of intracellular genes in PEDV-infected IPEC-J2 cells using transcriptomics. The results demonstrate that PEDV triggers autophagy via the cellular pathogen receptor TLR4 and the AKT-mTOR pathway. As evidenced by autophagosome detection, PEDV infection increases autophagosomes and light chain 3 (LC3)-II as well as downregulated AKT-mTOR phosphorylation. Our study revealed that the binding of the viral protein NSP61-2C (56-151aa) to TLR4 triggers autophagy and inactivates the AKT-mTOR pathway, both of which are critical for facilitating PEDV infection. Through screening and analysis, TLR4 was found to be a key gene involved in PEDV-induced autophagy. The screening of the key functional domains of NSP6 (56-151aa) for their ability to induce autophagy in IPEC-J2 cells provided a basis for the in-depth analysis of the pathogenic mechanism of PEDV infection-induced autophagy and promotion of self-replication and also provided an important target for the study of PEDV antiviral drugs. In conclusion, we elucidated that the PEDV infection of IPEC-J2 cells could induce autophagy and found that PEDV could use autophagy to promote its own replication. Full article

(This article belongs to the Section Animal Viruses)

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7 pages, 548 KiB

Open AccessCommunication

Respiratory Viral Infection Patterns in Hospitalised Children Before and After COVID-19 in Hong Kong

by Jason Chun Sang Pun, Kin Pong Tao, Stacy Lok Sze Yam, Kam Lun Hon, Paul Kay Sheung Chan, Albert Martin Li and Renee Wan Yi Chan

Viruses 2024, 16(11), 1786; https://doi.org/10.3390/v16111786 - 17 Nov 2024

Viewed by 388

Abstract

The study highlights the significant changes in respiratory virus epidemiology following the lifting of COVID-19 restrictions. Method: In this single-centre retrospective study, the virological readouts of adenovirus (AdV), influenza virus A (IAV), influenza virus B (IBV), parainfluenza viruses (PIV) 1, 2, 3, 4, [...] Read more.

The study highlights the significant changes in respiratory virus epidemiology following the lifting of COVID-19 restrictions. Method: In this single-centre retrospective study, the virological readouts of adenovirus (AdV), influenza virus A (IAV), influenza virus B (IBV), parainfluenza viruses (PIV) 1, 2, 3, 4, respiratory syncytial virus (RSV), and coupled enterovirus and rhinovirus (EV/RV) were extracted from the respiratory specimens of paediatric patients in Hong Kong from January 2015 to February 2024. The subjects were stratified into five age groups. Results: The study included 18,737 and 6001 respiratory specimens in the pre-COVID-19 and post-COVID-19 mask mandate period, respectively. The mean age of hospitalised patients increased from 3.49 y ± 0.03 y to 4.37 y ± 0.05 y after the COVID-19 lockdown. The rates of single-virus infection and co-infection were significantly higher in the post-COVID-19 mask mandate period. The odds ratio for AdV for all age groups (OR: 4.53, 4.03, 2.32, 2.46, 1.31) and RSV in older children from 3 years old and above (OR: 1.95, 3.38, p < 0.01) were significantly elevated after the COVID-19 outbreak. Conclusions: Our findings suggest that public health measures to contain COVID-19 may have unintended consequences on children’s natural exposure and immunity to other respiratory viruses, potentially increasing their morbidity in the post-pandemic era. Full article

(This article belongs to the Special Issue The Influence of COVID-19 Pandemic on the Epidemiology of Other Human Viral Infections)

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44 pages, 2124 KiB

Open AccessReview

Extracellular Vesicles in Viral Liver Diseases

by Elias Kouroumalis, Ioannis Tsomidis and Argyro Voumvouraki

Viruses 2024, 16(11), 1785; https://doi.org/10.3390/v16111785 - 17 Nov 2024

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Abstract

Extracellular vesicles (EVs) are bilayer vesicles released by cells in the microenvironment of the liver including parenchymal and non-parenchymal cells. They are the third important mechanism in the communications between cells, besides the secretion of cytokines and chemokines and the direct cell-to-cell contact. [...] Read more.

Extracellular vesicles (EVs) are bilayer vesicles released by cells in the microenvironment of the liver including parenchymal and non-parenchymal cells. They are the third important mechanism in the communications between cells, besides the secretion of cytokines and chemokines and the direct cell-to-cell contact. The aim of this review is to discuss the important role of EVs in viral liver disease, as there is increasing evidence that the transportation of viral proteins, all types of RNA, and viral particles including complete virions is implicated in the pathogenesis of both viral cirrhosis and viral-related hepatocellular carcinoma. The biogenesis of EVs is discussed and their role in the pathogenesis of viral liver diseases is presented. Their use as diagnostic and prognostic biomarkers is also analyzed. Most importantly, the significance of possible novel treatment strategies for liver fibrosis and hepatocellular carcinoma is presented, although available data are based on experimental evidence and clinical trials have not been reported. Full article

(This article belongs to the Section General Virology)

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16 pages, 3929 KiB

Open AccessArticle

HSPA4 Enhances BRSV Entry via Clathrin-Mediated Endocytosis Through Regulating the PI3K–Akt Signaling Pathway and ATPase Activity of HSC70

by Yang Liu, Qiongyi Li, Shuai Shao, Xiaolan Ji, Wanning Gao, Yiyang Fan, Mingqi Liu, Yan Wang and Jialin Bai

Viruses 2024, 16(11), 1784; https://doi.org/10.3390/v16111784 - 17 Nov 2024

Viewed by 443

Abstract

Bovine respiratory syncytial virus (BRSV) is an enveloped RNA virus that utilizes clathrin-mediated endocytosis for cell entry and is a significant pathogen in bovine respiratory disease (BRD). Heat shock protein family A member 4 (HSPA4), a member of the HSP70 family, is known [...] Read more.

Bovine respiratory syncytial virus (BRSV) is an enveloped RNA virus that utilizes clathrin-mediated endocytosis for cell entry and is a significant pathogen in bovine respiratory disease (BRD). Heat shock protein family A member 4 (HSPA4), a member of the HSP70 family, is known to be involved in the progression of various cancers. However, its role in virus entry has not been previously explored. Through experiments involving Western blot analysis, virus titer, and virus copies analysis, we demonstrated that HSPA4 can regulate BRSV entry and replication. The specific regulation mode is to enhance BRSV entry by promoting clathrin-mediated endocytosis. We used Western blot, virus titer, virus copies analysis, and IFA to demonstrate that HSPA4 can promote clathrin heavy chain protein (CHC) expression and further promote BRSV entry by activating the PI3K–Akt signaling pathway. Furthermore, we observed that HSPA4 boosts the efficiency of clathrin-mediated endocytosis by increasing the ATPase activity of heat shock cognate protein 70 (HSC70), thereby facilitating BRSV entry. Additionally, our investigation into the impact of HSPA4 on the entry of other viruses revealed that HSPA4 can facilitate the entry of a variety of viruses into host cells. Full article

(This article belongs to the Section Animal Viruses)

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21 pages, 3291 KiB

Open AccessArticle

NSC95397 Is a Novel HIV-1 Latency-Reversing Agent

by Randilea Nichols Doyle, Vivian Yang, Yetunde I. Kayode, Robert Damoiseaux, Harry E. Taylor and Oliver I. Fregoso

Viruses 2024, 16(11), 1783; https://doi.org/10.3390/v16111783 - 16 Nov 2024

Viewed by 389

Abstract

The latent viral reservoir represents one of the major barriers to curing HIV-1. Focus on the “kick and kill” (also called “shock and kill”) approach, in which virus expression is reactivated, and then cells producing virus are selectively depleted, has led to the [...] Read more.

The latent viral reservoir represents one of the major barriers to curing HIV-1. Focus on the “kick and kill” (also called “shock and kill”) approach, in which virus expression is reactivated, and then cells producing virus are selectively depleted, has led to the discovery of many latency-reversing agents (LRAs) that have furthered our understanding of the mechanisms driving HIV-1 latency and latency reversal. Thus far, individual compounds have yet to be robust enough to work as a therapy, highlighting the importance of identifying new compounds that target novel pathways and synergize with known LRAs. In this study, we identified a promising LRA, NSC95397, from a screen of ~4250 compounds. We validated that NSC95397 reactivates latent viral transcription and protein expression from cells with unique integration events and across different latency models. Co-treating cells with NSC95397 and known LRAs demonstrated that NSC95397 synergizes with different drugs under both standard normoxic and physiological hypoxic conditions. NSC95397 does not globally increase open chromatin, and bulk RNA sequencing revealed that NSC95397 does not greatly increase cellular transcription. Instead, NSC95397 downregulates pathways key to metabolism, cell growth, and DNA repair—highlighting the potential of these pathways in regulating HIV-1 latency. Overall, we identified NSC95397 as a novel LRA that does not largely alter global transcription, shows potential for synergy with known LRAs, and may act through novel pathways not previously recognized for their ability to modulate HIV-1 latency. Full article

(This article belongs to the Special Issue Unraveling the Pathogenesis of Persistent Virus Infection)

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15 pages, 301 KiB

Open AccessArticle

Prevalence of Plantar Warts, Genital Warts, and Herpetic Infections in Greek Competitive Swimmers

by Eleni Sfyri, Niki Tertipi, Vasiliki Kefala and Efstathios Rallis

Viruses 2024, 16(11), 1782; https://doi.org/10.3390/v16111782 - 16 Nov 2024

Viewed by 672

Abstract

Viral outbreaks are common in the sport community. Data regarding the prevalence of plantar warts, genital warts, herpes simplex type 1 (herpes labialis), herpes zoster, and genital herpes in competitive swimmers are lacking in the literature. The purpose of this study was to [...] Read more.

Viral outbreaks are common in the sport community. Data regarding the prevalence of plantar warts, genital warts, herpes simplex type 1 (herpes labialis), herpes zoster, and genital herpes in competitive swimmers are lacking in the literature. The purpose of this study was to determine the prevalence of those viral infections among young competitive swimmers participating in Greek swimming clubs. Swimmers’ parents and adult swimmers were asked to complete an anonymous questionnaire. In total, 1047 swimmers enrolled in this study. The measured parameters included gender, age, times of infections, and seasons when athletes may be more susceptible to infections. Practicing information such as type of swimming facility, number of training years, average hours of daily training, behaviors in swimming practice, and sunlight exposure was also recorded. All infections showed a significant difference in relation to “age” and “years of training”. The gender significance was observed in herpes labialis (p = 0.016) and plantar warts (p = 0.05). The prevalence of all infections in swimmers who use outdoor facilities was higher. Certain behaviors such as walking barefoot on a pool deck and sharing swimming equipment correlate with herpes simplex and plantar warts. Virus infections can affect swimmers of all ages. In our study, plantar warts and herpes labialis are more common in swimmers. Herpes zoster and sexually transmitted viruses are rarer and affect adult swimmers. The impact of cutaneous infections on swimmers can affect performance and well-being. Effective prevention and management are essential to avoid complications. Proper hygiene, medical guidance, and treatment reduce swimmers’ exposure to skin viruses. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Clinical Manifestations of Persistent Viral Infections)

13 pages, 1012 KiB

Open AccessReview

Cytomegalovirus Infection After Solid Organ Transplantation: How I Use Cell-Mediated Immune Assays for Management

by Raymund R. Razonable

Viruses 2024, 16(11), 1781; https://doi.org/10.3390/v16111781 - 15 Nov 2024

Viewed by 718

Abstract

Introduction: The pathogenesis and outcome of cytomegalovirus (CMV) infection after solid organ transplantation (SOT) reflects the interplay between viral replication and CMV-specific immunity. Despite advances in its diagnosis and treatment, CMV continues to cause significant morbidity after SOT. Since CMV is an opportunistic [...] Read more.

Introduction: The pathogenesis and outcome of cytomegalovirus (CMV) infection after solid organ transplantation (SOT) reflects the interplay between viral replication and CMV-specific immunity. Despite advances in its diagnosis and treatment, CMV continues to cause significant morbidity after SOT. Since CMV is an opportunistic pathogen that occurs as a result of impaired pathogen-specific immunity, laboratory assays that measure CMV-specific immune responses may be useful in assisting clinicians in its management. Methods and Results: The author summarizes the evolving and emerging data on the clinical utility of assays that quantify cell-mediated immune responses to CMV in SOT recipients. The majority of publications are observational studies that demonstrate that a lack or deficiency in CMV-specific cell-mediated immunity is correlated with a heightened risk of primary, reactivation, or recurrent CMV after transplantation. A few prospective interventional studies have utilized CMV-specific cell-mediated immune assays in guiding the duration of antiviral prophylaxis among CMV-seropositive SOT recipients. Likewise, CMV-specific cell-mediated immunity assays have been suggested to inform the need for secondary antiviral prophylaxis and immunologic optimization to prevent CMV relapse after treatment. Conclusions: CMV-specific cell-mediated immune assays are emerging to assist transplant clinicians in predicting a patient’s risk of CMV after transplantation, and these assays have been utilized to individualize the approach to CMV prevention and treatment. The author suggests the conduct of more interventional studies to further solidify the role of CMV-specific cell-mediated immune assays in routine clinical practice. Full article

(This article belongs to the Special Issue Viral Infections in Immunocompromised Hosts)

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13 pages, 3512 KiB

Open AccessArticle

Identification and Characterization of Linear Epitopes of Monoclonal Antibodies Against African Horse Sickness Virus Serotype 1 VP2 Protein

by Xiaohua Ma, Yingzhi Zhang, Lei Na, Ting Qi, Weiwei Ma, Xing Guo, Xue-Feng Wang and Xiaojun Wang

Viruses 2024, 16(11), 1780; https://doi.org/10.3390/v16111780 - 15 Nov 2024

Viewed by 346

Abstract

African horse sickness (AHS) is an acute, fatal, contagious disease of animals of the family Equidae and is caused by infection with the African horse sickness virus (AHSV). Based on the outer capsid protein VP2, AHSV is classified into nine serotypes (AHSV−1 to [...] Read more.

African horse sickness (AHS) is an acute, fatal, contagious disease of animals of the family Equidae and is caused by infection with the African horse sickness virus (AHSV). Based on the outer capsid protein VP2, AHSV is classified into nine serotypes (AHSV−1 to −9) with little or no serological cross-reactivity between them. In 2020, AHS outbreaks caused by AHSV−1 were reported in Thailand and Malaysia, marking the first occurrences of AHS in Southeast Asia. However, little is known about the antigenic profile of AHSV−1 VP2. In this study, a recombinant VP2 protein was expressed in Escherichia coli and used as an immunogen, and three monoclonal antibodies (mAbs), designated 7D11, 10A9, and 9E7, against AHSV−1 VP2, were generated. These three mAbs were then successfully used in IFA, WB, and ELISA for the detection of AHSV−1 VP2. Two overlapping linear epitopes, ⁶⁷⁰NEFDFE⁶⁷⁵ (E670–675) recognized by 9E7 and ⁶⁷⁰NEFDF⁶⁷⁴ (E670–674) recognized by 7D11 and 10A9, were identified through truncation of GST-fused VP2. Amino acid sequence alignment shows that the ⁶⁷⁰NEFDFE⁶⁷⁵ motif is completely conserved within AHSV−1 but is highly divergent in other AHSV serotypes. Our studies provide an important tool for basic research into AHSV−1 and for the diagnosis of AHSV−1. Full article

(This article belongs to the Section Animal Viruses)

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20 pages, 11059 KiB

Open AccessArticle

Single-Nucleus and Spatial Transcriptomics Revealing Host Response Differences Triggered by Mutated Virus in Severe Dengue

by Qian Chen, Yizhen Yuan, Fangzhou Cai, Zhe Li, Qiang Wei and Wei Wang

Viruses 2024, 16(11), 1779; https://doi.org/10.3390/v16111779 - 15 Nov 2024

Viewed by 369

Abstract

Dengue virus (DENV) infection causes various disease manifestations ranging from an asymptomatic state to severe, life-threatening dengue. Despite intensive research, the molecular mechanisms underlying the abnormal host responses and severe disease symptoms caused by evolved DENV strains is not fully understood. First, the [...] Read more.

Dengue virus (DENV) infection causes various disease manifestations ranging from an asymptomatic state to severe, life-threatening dengue. Despite intensive research, the molecular mechanisms underlying the abnormal host responses and severe disease symptoms caused by evolved DENV strains is not fully understood. First, the spatial structure of mutant DENV was compared via in silico molecular modeling analysis. Second, employing single-nucleus and spatial RNA sequencing, we analyzed and verified transcriptome samples in uninfected, mild (NGC group), and severe (N10 group) liver tissues from murine models. In this study, we obtained a cumulatively mutated DENV-2 N10 with enhanced capability of replication and pathogenicity post 10 serial passages in Ifnra^−/− mice. This variant caused severe damage in the liver, as compared with other organs. Furthermore, mutated DENV infection elicited stronger responses in hepatocytes. The critical host factor Nrg4 was identified. It dominated mainly via the activation of the NRG/ErbB pathway in mice with severe symptoms. We report on evolved N10 viruses with changes observed in different organisms and tissue. This evolutionary variant results in high replicability, severe pathogenicity, and strong responses in murine. Moreover, the host responses may play a role by activating the NRG/ErbB signaling pathway. Our findings provide a realistic framework for defining disturbed host responses at the animal model level that might be one of the main causes of severe dengue and the potential application value. Full article

(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)

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26 pages, 444 KiB

Open AccessReview

Arbovirus in Solid Organ Transplants: A Narrative Review of the Literature

by Kiran Gajurel, Reshika Dhakal and Stan Deresinski

Viruses 2024, 16(11), 1778; https://doi.org/10.3390/v16111778 - 15 Nov 2024

Viewed by 609

Abstract

The incidence of arbovirus infections has increased in recent decades. Other than dengue, chikungunya, and West Nile viruses, the data on arbovirus in solid organ transplant (SOT) are limited to case reports, and infections in renal transplant recipients account for most of the [...] Read more.

The incidence of arbovirus infections has increased in recent decades. Other than dengue, chikungunya, and West Nile viruses, the data on arbovirus in solid organ transplant (SOT) are limited to case reports, and infections in renal transplant recipients account for most of the reported cases. Dengue and West Nile infections seem to be more severe with higher mortality in SOT patients than in the general population. Acute kidney injury is more frequent in patients with dengue and chikungunya although persistent arthralgia with the latter is less frequent. There is no clear relationship between arboviral infection and acute cellular rejection. Pre-transplant screening of donors should be implemented during increased arboviral activity but, despite donor screening and negative donor nucleic acid amplification test (NAT), donor derived infection can occur. NAT may be transiently positive. IgM tests lack specificity, and neutralizing antibody assays are more specific but not readily available. Other tests, such as immunohistochemistry, antigen tests, PCR, metagenomic assays, and viral culture, can also be performed. There are a few vaccines available against some arboviruses, but live vaccines should be avoided. Treatment is largely supportive. More data on arboviral infection in SOT are needed to understand its epidemiology and clinical course. Full article

(This article belongs to the Special Issue Viral Infections in Immunocompromised Hosts)

12 pages, 7492 KiB

Open AccessArticle

Porcine Airway Organoid-Derived Well-Differentiated Epithelial Cultures as a Tool for the Characterization of Swine Influenza a Virus Strains

by Nora M. Gerhards, Manouk Vrieling, Romy Dresken, Sophie Nguyen-van Oort, Luca Bordes, Jerry M. Wells and Rik L. de Swart

Viruses 2024, 16(11), 1777; https://doi.org/10.3390/v16111777 - 15 Nov 2024

Viewed by 386

Abstract

Swine influenza A viruses (IAVsw) are important causes of disease in pigs but also constitute a public health risk. IAVsw strains show remarkable differences in pathogenicity. We aimed to generate airway organoids from the porcine lower respiratory tract and use these to establish [...] Read more.

Swine influenza A viruses (IAVsw) are important causes of disease in pigs but also constitute a public health risk. IAVsw strains show remarkable differences in pathogenicity. We aimed to generate airway organoids from the porcine lower respiratory tract and use these to establish well-differentiated airway epithelial cell (WD-AEC) cultures grown at an air–liquid interface (ALI) for in vitro screening of IAVsw strain virulence. Epithelial cells were isolated from bronchus tissue of juvenile pigs, and airway organoids were cultured in an extracellular matrix in a culture medium containing human growth factors. Single-cell suspensions of these 3D organoids were seeded on Transwell filters and differentiated at ALI to form a pseudostratified epithelium containing ciliated cells, mucus-producing cells and tight junctions. Inoculation with a low dose of IAVsw in a low volume inoculum resulted in virus replication without requiring the addition of trypsin, and was quantified by the detection of viral genome loads in apical washes. Interestingly, inoculation of an H3N2 strain known to cause severe disease in pigs induced a greater reduction in trans-epithelial resistance and more damage to tight junctions than H1N2 or H1N1 strains associated with mild disease in pigs. We conclude that the porcine WD-AEC model is useful in assessing the virulence of IAVsw strains. Full article

(This article belongs to the Special Issue Endemic and Emerging Swine Viruses 2024)

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26 pages, 7300 KiB

Open AccessArticle

Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses

by Harry Ridgway, Vasso Apostolopoulos, Graham J. Moore, Laura Kate Gadanec, Anthony Zulli, Jordan Swiderski, Sotirios Tsiodras, Konstantinos Kelaidonis, Christos T. Chasapis and John M. Matsoukas

Viruses 2024, 16(11), 1776; https://doi.org/10.3390/v16111776 - 14 Nov 2024

Viewed by 950

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus (RSV) are significant global health threats. The need for low-cost, easily synthesized oral drugs for rapid deployment during outbreaks is crucial. Broad-spectrum therapeutics, or pan-antivirals, are designed to target multiple viral [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus (RSV) are significant global health threats. The need for low-cost, easily synthesized oral drugs for rapid deployment during outbreaks is crucial. Broad-spectrum therapeutics, or pan-antivirals, are designed to target multiple viral pathogens simultaneously by focusing on shared molecular features, such as common metal cofactors or conserved residues in viral catalytic domains. This study introduces a new generation of potent sartans, known as bisartans, engineered in our laboratories with negative charges from carboxylate or tetrazolate groups. These anionic tetrazoles interact strongly with cationic arginine residues or metal cations (e.g., Zn²⁺) within viral and host target sites, including the SARS-CoV-2 ACE2 receptor, influenza H1N1 neuraminidases, and the RSV fusion protein. Using virtual ligand docking and molecular dynamics, we investigated how bisartans and their analogs bind to these viral receptors, potentially blocking infection through a pan-antiviral mechanism. Bisartan, ACC519TT, demonstrated stable and high-affinity docking to key catalytic domains of the SARS-CoV-2 NSP3, H1N1 neuraminidase, and RSV fusion protein, outperforming FDA-approved drugs like Paxlovid and oseltamivir. It also showed strong binding to the arginine-rich furin cleavage sites S1/S2 and S2′, suggesting interference with SARS-CoV-2’s spike protein cleavage. The results highlight the potential of tetrazole-based bisartans as promising candidates for developing broad-spectrum antiviral therapies. Full article

(This article belongs to the Special Issue Molecular Epidemiology of SARS-CoV-2, 3rd Edition)

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23 pages, 1586 KiB

Open AccessReview

Oncolytic Virotherapies and Adjuvant Gut Microbiome Therapeutics to Enhance Efficacy Against Malignant Gliomas

by Natalie M. Meléndez-Vázquez, Candelaria Gomez-Manzano and Filipa Godoy-Vitorino

Viruses 2024, 16(11), 1775; https://doi.org/10.3390/v16111775 - 14 Nov 2024

Viewed by 689

Abstract

Glioblastoma (GBM) is the most prevalent malignant brain tumor. Current standard-of-care treatments offer limited benefits for patient survival. Virotherapy is emerging as a novel strategy to use oncolytic viruses (OVs) for the treatment of GBM. These engineered and non-engineered viruses infect and lyse [...] Read more.

Glioblastoma (GBM) is the most prevalent malignant brain tumor. Current standard-of-care treatments offer limited benefits for patient survival. Virotherapy is emerging as a novel strategy to use oncolytic viruses (OVs) for the treatment of GBM. These engineered and non-engineered viruses infect and lyse cancer cells, causing tumor destruction without harming healthy cells. Recent advances in genetic modifications to OVs have helped improve their targeting capabilities and introduce therapeutic genes, broadening the therapeutic window and minimizing potential side effects. The efficacy of oncolytic virotherapy can be enhanced by combining it with other treatments such as immunotherapy, chemotherapy, or radiation. Recent studies suggest that manipulating the gut microbiome to enhance immune responses helps improve the therapeutic efficacy of the OVs. This narrative review intends to explore OVs and their role against solid tumors, especially GBM while emphasizing the latest technologies used to enhance and improve its therapeutic and clinical responses. Full article

(This article belongs to the Special Issue Progress and Prospects in Oncolytic Virotherapy)

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25 pages, 2482 KiB

Open AccessReview

The Immune Escape Strategy of Rabies Virus and Its Pathogenicity Mechanisms

by Abraha Bahlbi Kiflu

Viruses 2024, 16(11), 1774; https://doi.org/10.3390/v16111774 - 14 Nov 2024

Viewed by 1086

Abstract

In contrast to most other rhabdoviruses, which spread by insect vectors, the rabies virus (RABV) is a very unusual member of the Rhabdoviridae family, since it has evolved to be fully adapted to warm-blooded hosts and spread directly between them. There are differences [...] Read more.

In contrast to most other rhabdoviruses, which spread by insect vectors, the rabies virus (RABV) is a very unusual member of the Rhabdoviridae family, since it has evolved to be fully adapted to warm-blooded hosts and spread directly between them. There are differences in the immune responses to laboratory-attenuated RABV and wild-type rabies virus infections. Various investigations showed that whilst laboratory-attenuated RABV elicits an innate immune response, wild-type RABV evades detection. Pathogenic RABV infection bypasses immune response by antagonizing interferon induction, which prevents downstream signal activation and impairs antiviral proteins and inflammatory cytokines production that could eliminate the virus. On the contrary, non-pathogenic RABV infection leads to immune activation and suppresses the disease. Apart from that, through recruiting leukocytes into the central nervous system (CNS) and enhancing the blood–brain barrier (BBB) permeability, which are vital factors for viral clearance and protection, cytokines/chemokines released during RABV infection play a critical role in suppressing the disease. Furthermore, early apoptosis of neural cells limit replication and spread of avirulent RABV infection, but street RABV strains infection cause delayed apoptosis that help them spread further to healthy cells and circumvent early immune exposure. Similarly, a cellular regulation mechanism called autophagy eliminates unused or damaged cytoplasmic materials and destroy microbes by delivering them to the lysosomes as part of a nonspecific immune defense mechanism. Infection with laboratory fixed RABV strains lead to complete autophagy and the viruses are eliminated. But incomplete autophagy during pathogenic RABV infection failed to destroy the viruses and might aid the virus in dodging detection by antigen-presenting cells, which could otherwise elicit adaptive immune activation. Pathogenic RABV P and M proteins, as well as high concentration of nitric oxide, which is produced during rabies virus infection, inhibits activities of mitochondrial proteins, which triggers the generation of reactive oxygen species, resulting in oxidative stress, contributing to mitochondrial malfunction and, finally, neuron process degeneration. Full article

(This article belongs to the Special Issue Viral Infections and Immune Dysregulation 2024)

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