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Special Issue "Coxsackieviruses and Associated Diseases"

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: 1 November 2023 | Viewed by 5803

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Prof. Dr. Laurent Andreoletti

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Guest Editor

1. Cardiovir EA-4684, UFR Médecine, Université de Reims Champagne-Ardenne, 51100 Reims, France
2. Virology Department, CHU Reims, Hôpital Robert Debré, 51100 Reims, France
Interests: group B enterovirus; viral cardiovascular; coxsackieviruses
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Didier Hober

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Laboratoire de Virologie ULR3610, University of Lille, CHU Lille, 59000 Lille, France
Interests: enterovirus; coxsackieviruses; viral pathogenesis
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Yong Zhang

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WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory for Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
Interests: human enterovirus disease; molecular evolution and epidemiology; coxsackieviruses

Special Issue Information

Dear Colleagues,

Human Coxsackie viruses (CV), including groups A & B (Picornaviridae), are ubiquitous single-stranded RNA-positive human pathogens. Their ability to utilize various cell receptors explains their widespread tissue tropism and their incredibly diverse pathogenicity. Their great capacity for genetic evolution has made them pathogens with a high potential for emergence. These viruses can modulate the innate defense mechanisms of the target cell, as well as the functionality of immune system cells, promoting immune system evasion. Currently, the mechanisms underlying CVs’ genetic evolution and modulation of inflammatory and immune responses remain to be explored, and their elucidation is critical for the development of future therapeutic or vaccine strategies.

This Special Issue aims to provide relevant data on: molecular evolution and mechanisms concerning the emergence of CV strains; the impact of these new genetic variants on human pathophysiology mechanisms, including inflammatory and immunological responses; CV pathogenicity and pathogenesis; antiviral drugs and resistance; and perspectives on improving translational research in infectious disease. We anticipate the reports collected in this issue will be of considerable interest and value to the scientific, clinical, and public health communities, and hope their publication will stimulate the development of further new therapeutic and vaccinal strategies against these major human pathogens.

Prof. Dr. Laurent Andreoletti
Prof. Dr. Didier Hober
Prof. Dr. Yong Zhang
Guest Editors

Manuscript Submission Information

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Published Papers (6 papers)

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Research

Open AccessArticle

Appendectomy Mitigates Coxsackievirus B3−Induced Viral Myocarditis

Chengrui Niu

Wei Xu

and

Sidong Xiong

Viruses 2023, 15(10), 1974; https://doi.org/10.3390/v15101974 - 22 Sep 2023

Viewed by 163

Abstract

Appendix has a distinct abundance of lymphatic cells and serves as a reservoir of microbiota which helps to replenish the large intestine with healthy flora. And it is the primary site of IgA induction, which shapes the composition of the intestinal microbiota. Recent population-based cohort studies report that appendectomy is associated with an increased risk of acute myocardial infarction and ischemic heart disease. Here, whether appendectomy has an effect on the occurrence and development of coxsackievirus B3 (CVB3)−induced viral myocarditis is studied. 10³ TCID₅₀ CVB3 was inoculated i.p. into appendectomized and sham-operated mice. RNA levels of viral load and pro-inflammatory cytokines in the hearts and the intestine were detected by RT−PCR. Compared to sham-operated mice, appendectomized mice exhibited attenuated cardiac inflammation and improved cardiac function, which is associated with a systemic reduced viral load. Appendectomized mice also displayed a reduction in cardiac neutrophil and macrophage infiltration and pro-inflammatory cytokine production. Mechanistically, we found that CVB3 induced an early and potent IL-10 production in the cecal patch at 2 days post infection. Appendectomy significantly decreased intestinal IL-10 and IL-10⁺ CD4⁺ Treg frequency which led to a marked increase in intestinal (primary entry site for CVB3) anti-viral IFN-γ⁺ CD4⁺ T and IFN-γ⁺ CD8⁺ T response and viral restriction, eventually resulting in improved myocarditis. Our results suggest that appendix modulates cardiac infection and inflammation through regulating intestinal IL-10⁺ Treg response. Full article

(This article belongs to the Special Issue Coxsackieviruses and Associated Diseases)

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Open AccessArticle

Reporter Coxsackievirus A5 Expressing iLOV Fluorescent Protein or Luciferase Used for Rapid Neutralizing Assay in Cells and Living Imaging in Mice

and

Viruses 2023, 15(9), 1868; https://doi.org/10.3390/v15091868 - 02 Sep 2023

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Abstract

Coxsackievirus A5 (CV-A5) is a re-emerging enterovirus that causes hand, foot, and mouth disease in children under five years of age. CV-A5-M14-611 is a mouse-adapted strain that can infect orally and lead to the death of 14-day-old mice. Here, recombinants based on CV-A5-M14-611 were constructed carrying three reporter genes in different lengths. Smaller fluorescent marker proteins, light, oxygen, voltage sensing (iLOV), and nano luciferase (Nluc) were proven to be able to express efficiently in vitro. However, the recombinant with the largest insertion of the red fluorescence protein gene (DsRed) was not rescued. The construction strategy of reporter viruses was to insert the foreign genes between the C-terminus of VP1 and the N-terminus of 2A genes and to add a 2A protease cleavage domain at both ends of the insertions. The iLOV-tagged or Nluc-tagged recombinants, CV-A5-iLOV or CV-A5-Nluc, exhibited a high capacity for viral replication, genetic stability in cells and pathogenicity in mice. They were used to establish a rapid, inexpensive and convenient neutralizing antibody assay and greatly facilitated virus neutralizing antibody titration. Living imaging was performed on mice with CV-A5-Nluc, which exhibited specific bioluminescence in virus-disseminated organs, while fluorescence induced by CV-A5-iLOV was weakly detected. The reporter-gene-tagged CV-A5 can be used to study the infection and mechanisms of CV-A5 pathogenicity in a mouse model. They can also be used to establish rapid and sensitive assays for detecting neutralizing antibodies. Full article

(This article belongs to the Special Issue Coxsackieviruses and Associated Diseases)

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Open AccessArticle

Epidemiology of Hand, Foot, and Mouth Disease and Genetic Evolutionary Characteristics of Coxsackievirus A10 in Taiyuan City, Shanxi Province from 2016 to 2020

and

Viruses 2023, 15(3), 694; https://doi.org/10.3390/v15030694 - 07 Mar 2023

Cited by 2 | Viewed by 795

Abstract

In recent years, the prevalence of hand, foot, and mouth disease (HFMD) caused by enteroviruses other than enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16) has gradually increased. The throat swab specimens of 2701 HFMD cases were tested, the VP1 regions of CVA10 RNA were amplified using RT-PCR, and phylogenetic analysis of CVA10 was performed. Children aged 1–5 years accounted for the majority (81.65%) and boys were more than girls. The positivity rates of EV-A71, CVA16, and other EVs were 15.22% (219/1439), 28.77% (414/1439), and 56.01% (806/1439), respectively. CVA10 is one of the important viruses of other EVs. A total of 52 CVA10 strains were used for phylogenetic analysis based on the VP1 region, 31 were from this study, and 21 were downloaded from GenBank. All CVA10 sequences could be assigned to seven genotypes (A, B, C, D, E, F, and G), and genotype C was further divided into C1 and C2 subtypes, only one belonged to subtype C1 and the remaining 30 belonged to C2 in this study. This study emphasized the importance of strengthening the surveillance of HFMD to understand the mechanisms of pathogen variation and evolution, and to provide a scientific basis for HFMD prevention, control, and vaccine development. Full article

(This article belongs to the Special Issue Coxsackieviruses and Associated Diseases)

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Open AccessArticle

Genomic Epidemiology and Transmission Dynamics of Global Coxsackievirus B4

and

Viruses 2023, 15(2), 569; https://doi.org/10.3390/v15020569 - 19 Feb 2023

Viewed by 997

Abstract

The aim of this study was to determine the global genetic diversity and transmission dynamics of coxsackievirus B4 (CVB4) and to propose future directions for disease surveillance. Next-generation sequencing was performed to obtain the complete genome sequence of CVB4, and the genetic diversity and transmission dynamics of CVB4 worldwide were analyzed using bioinformatics methods such as phylogenetic analysis, evolutionary dynamics, and phylogeographic analysis. Forty complete genomes of CVB4 were identified from asymptomatic infected individuals and hand, foot, and mouth disease (HFMD) patients. Frequent recombination between CVB4 and EV-B multiple serotypes in the 3D^pol region was found and formed 12 recombinant patterns (A-L). Among these, the CVB4 isolated from asymptomatic infected persons and HFMD patients belonged to lineages H and I, respectively. Transmission dynamics analysis based on the VP1 region revealed that CVB4 epidemics in countries outside China were dominated by the D genotype, whereas the E genotype was dominant in China, and both genotypes evolved at a rate of > 6.50 × 10⁻³ substitutions/site/year. CVB4 spreads through the population unseen, with the risk of disease outbreaks persisting as susceptible individuals accumulate. Our findings add to publicly available CVB4 genomic sequence data and deepen our understanding of CVB4 molecular epidemiology. Full article

(This article belongs to the Special Issue Coxsackieviruses and Associated Diseases)

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Open AccessArticle

Coxsackievirus A6 Infection Causes Neurogenic Pathogenesis in a Neonatal Murine Model

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Viruses 2023, 15(2), 511; https://doi.org/10.3390/v15020511 - 12 Feb 2023

Cited by 1 | Viewed by 1281

Abstract

Coxsackievirus A6 (CVA6), a member of species A enterovirus, is associated with outbreaks of hand-foot-and-mouth disease and causes a large nationwide burden of disease. However, the molecular pathogenesis of CVA6 remains unclear. In the present study, we established a suckling Institute of Cancer Research (ICR) mouse infection model to explore the neural pathogenicity of CVA6. Five-day-old mice infected with CVA6 strain F219 showed lethargy and paralysis, and died 5 or 6 days after infection via IM injection. Cerebral edema and neuronal cell swelling were observed in the infected brain tissue, and we found that the CVA6 VP1 antigen could co-localize with GFAP-positive astrocytes in infected mouse brain using an immunofluorescence assay. CVA6 strain F219 can also infect human glioma (U251) cells. Transcriptome analysis of brain tissues from infected mice and infected U251 cells showed that significantly differentially expressed genes were enriched in antiviral and immune response and neurological system processes. These results indicate that CVA6 could cause neural pathogenesis and provide basic data for exploring the mechanism of how host–cell interactions affect viral replication and pathogenesis. Importance: Coxsackievirus A6 (CVA6) surpasses the two main pathogens, enterovirus 71 (EV-A71) and coxsackievirus A16 (CVA16), which are the leading pathogens causing HFMD in many provinces of China. In our study, CVA6 infection caused neurogenic pathogenesis in a neonatal murine model, manifesting as cerebral edema and neuronal cell swelling, CVA6 VP1 antigen could co-localize with GFAP-positive astrocytes in the infected mouse brain. Based on CVA6-infected brain tissue and U251 cell transcriptome analysis, we found upregulated antiviral and immune response-related genes such as Zbp1, Usp18, Oas2, Irf7, Ddx60, Ifit3, Ddx58, and Isg15, while the neurological system process-related genes were downregulated, including Fcrls, Ebnrb, Cdk1, and Anxa5. Full article

(This article belongs to the Special Issue Coxsackieviruses and Associated Diseases)

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Open AccessArticle

Evolutionary and Genetic Recombination Analyses of Coxsackievirus A6 Variants Associated with Hand, Foot, and Mouth Disease Outbreaks in Thailand between 2019 and 2022

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Viruses 2023, 15(1), 73; https://doi.org/10.3390/v15010073 - 27 Dec 2022

Cited by 1 | Viewed by 1806

Abstract

Coxsackievirus (CV)-A6 infections cause hand, foot, and mouth disease (HFMD) in children and adults. Despite the serious public health threat presented by CV-A6 infections, our understanding of the mechanisms by which new CV-A6 strains emerge remains limited. This study investigated the molecular epidemiological trends, evolutionary dynamics, and recombination characteristics of CV-A6-associated HFMD in Thailand between 2019 and 2022. In the HFMD patient samples collected during the 4-year study period, we identified enterovirus (EV) RNA in 368 samples (48.7%), of which CV-A6 (23.7%) was the predominant genotype, followed by CV-A4 (6%), EV-A71 (3.7%), and CV-A16 (3.4%). According to the partial viral protein (VP) 1 sequences, all these CV-A6 strains belonged to the D3 clade. Based on the viral-RNA-dependent RNA polymerase (RdRp) gene, four recombinant forms (RFs), RF-A (147, 84.5%), RF-N (11, 6.3%), RF-H (1, 0.6%), and newly RF-Y (15, 8.6%), were identified throughout the study period. Results from the similarity plot and bootscan analyses revealed that the 3D polymerase (3Dpol) region of the D3/RF-Y subclade consists of sequences highly similar to CV-A10. We envisage that the epidemiological and evolutionarily insights presented in this manuscript will contribute to the development of vaccines to prevent the spread of CV-A6 infection. Full article

(This article belongs to the Special Issue Coxsackieviruses and Associated Diseases)

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