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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: 30 June 2024 | Viewed by 13367

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Prof. Dr. Laurent Andreoletti

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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
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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

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Research

15 pages, 1490 KiB

Open AccessArticle

Non-Polio Enteroviruses Isolated by Acute Flaccid Paralysis Surveillance Laboratories in the Russian Federation in 1998–2021: Distinct Epidemiological Features of Types

by Olga E. Ivanova, Tatiana P. Eremeeva, Nadezhda S. Morozova, Yulia M. Mikhailova, Liubov I. Kozlovskaya, Olga Y. Baikova, Armen K. Shakaryan, Alexandr Y. Krasota, Ekaterina A. Korotkova, Elizaveta V. Yakovchuk, Elena Y. Shustova and Alexander N. Lukashev

Viruses 2024, 16(1), 135; https://doi.org/10.3390/v16010135 - 18 Jan 2024

Viewed by 957

Abstract

More than 100 types of non-polio enteroviruses (NPEVs) are ubiquitous in the human population and cause a variety of symptoms ranging from very mild to meningitis and acute flaccid paralysis (AFP). Much of the information regarding diverse pathogenic properties of NPEVs comes from the surveillance of poliovirus, which also yields NPEV. The analysis of 265 NPEV isolations from 10,433 AFP cases over 24 years of surveillance and more than 2500 NPEV findings in patients without severe neurological lesions suggests that types EV-A71, E13, and E25 were significantly associated with AFP. EV-A71 was also significantly more common among AFP patients who had fever at the onset and residual paralysis compared to all AFP cases. In addition, a significant disparity was noticed between types that were common in humans (CV-A2, CVA9, EV-A71, E9, and E30) or in sewage (CVA7, E3, E7, E11, E12, and E19). Therefore, there is significant evidence of non-polio viruses being implicated in severe neurological lesions, but further multicenter studies using uniform methodology are needed for a definitive conclusion. Full article

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

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15 pages, 7200 KiB

Open AccessArticle

Molecular Epidemiology and Evolution of Coxsackievirus A14

by Liheng Yu, Qin Guo, Haiyan Wei, Yingying Liu, Wenbin Tong, Shuangli Zhu, Tianjiao Ji, Qian Yang, Dongyan Wang, Jinbo Xiao, Huanhuan Lu, Ying Liu, Jichen Li, Wenhui Wang, Yun He, Yong Zhang and Dongmei Yan

Viruses 2023, 15(12), 2323; https://doi.org/10.3390/v15122323 - 26 Nov 2023

Viewed by 1084

Abstract

As the proportion of non-enterovirus 71 and non-coxsackievirus A16 which proportion of composition in the hand, foot, and mouth pathogenic spectrum gradually increases worldwide, the attention paid to other enteroviruses has increased. As a member of the species enterovirus A, coxsackievirus A14 (CVA14) has been epidemic around the world until now since it has been isolated. However, studies on CVA14 are poor and the effective population size, evolutionary dynamics, and recombination patterns of CVA14 are not well understood. In this study, 15 CVA14 strains were isolated from HFMD patients in mainland China from 2009 to 2019, and the complete sequences of CVA14 in GenBank as research objects were analyzed. CVA14 was divided into seven genotypes A-G based on an average nucleotide difference of the full-length VP1 coding region of more than 15%. Compared with the CVA14 prototype strain, the 15 CVA14 strains showed 84.0–84.7% nucleotide identity in the complete genome and 96.9–97.6% amino acid identity in the encoding region. Phylodynamic analysis based on 15 CVA14 strains and 22 full-length VP1 sequences in GenBank showed a mean substitution rate of 5.35 × 10⁻³ substitutions/site/year (95% HPD: 4.03–6.89 × 10⁻³) and the most recent common ancestor (tMRCA) of CVA14 dates back to 1942 (95% HPD: 1930–1950). The Bayesian skyline showed that the effective population size had experienced a decrease–increase–decrease fluctuation since 2004. The phylogeographic analysis indicated two and three possible migration paths in the world and mainland China, respectively. Four recombination patterns with others of species enterovirus A were observed in 15 CVA14 strains, among which coxsackievirus A2 (CVA2), coxsackievirus A4 (CVA4), coxsackievirus A6 (CVA6), coxsackievirus A8 (CVA8), and coxsackievirus A12 (CVA12) may act as recombinant donors in multiple regions. This study has filled the gap in the molecular epidemiological characteristics of CVA14, enriched the global CVA14 sequence database, and laid the epidemiological foundation for the future study of CVA14 worldwide. Full article

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

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15 pages, 4388 KiB

Open AccessArticle

Identification of Critical Amino Acids of Coxsackievirus A10 Associated with Cell Tropism and Viral RNA Release during Uncoating

by Jie Pei, Rui-Lun Liu, Zhi-Hui Yang, Ya-Xin Du, Sha-Sha Qian, Sheng-Li Meng, Jing Guo, Bo Zhang and Shuo Shen

Viruses 2023, 15(10), 2114; https://doi.org/10.3390/v15102114 - 18 Oct 2023

Viewed by 1117

Abstract

Coxsackievirus A10 (CV-A10) is a prevailing causative agent of hand–foot–mouth disease, necessitating the isolation and adaptation of appropriate strains in cells allowed for human vaccine development. In this study, amino acid sequences of CV-A10 strains with different cell tropism on RD and Vero cells were compared. Various amino acids on the structural and non-structural proteins related to cell tropism were identified. The reverse genetic systems of several CV-A10 strains with RD⁺/Vero⁻ and RD⁺/Vero⁺ cell tropism were developed, and a set of CV-A10 recombinants were produced. The binding, entry, uncoating, and proliferation steps in the life cycle of these viruses were evaluated. P1 replacement of CV-A10 strains with different cell tropism revealed the pivotal role of the structural proteins in cell tropism. Further, seven amino acid substitutions in VP2 and VP1 were introduced to further investigate their roles played in cell tropism. These mutations cooperated in the growth of CV-A10 in Vero cells. Particularly, the valine to isoleucine mutation at the position VP1-236 (V1236I) was found to significantly restrict viral uncoating in Vero cells. Co-immunoprecipitation assays showed that the release of viral RNA from the KREMEN1 receptor-binding virions was restricted in r0195-V1236I compared with the parental strain r0195 (a RD⁺/Vero⁺ strain). Overall, this study highlights the dominant effect of structural proteins in CV-A10 adaption in Vero cells and the importance of V1236 in viral uncoating, providing a foundation for the mechanism study of CV-A10 cell tropism, and facilitating the development of vaccine candidates. Full article

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

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13 pages, 2253 KiB

Open AccessArticle

Appendectomy Mitigates Coxsackievirus B3−Induced Viral Myocarditis

by Chengrui Niu, Wei Xu and Sidong Xiong

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

Viewed by 1047

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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15 pages, 2737 KiB

Open AccessArticle

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

by Wei-Ping Jin, Chen Wang, Jie Wu, Jing Guo, Sheng-Li Meng, Ze-Jun Wang, Dai-Guan Yu and Shuo Shen

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

Viewed by 1009

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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11 pages, 1618 KiB

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

by Jitao Wang, Hongyan Liu, Zijun Cao, Jihong Xu, Jiane Guo, Lifeng Zhao, Rui Wang, Yang Xu, Ruihong Gao, Li Gao, Zhihong Zuo, Jinbo Xiao, Huanhuan Lu and Yong Zhang

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

Cited by 4 | Viewed by 1276

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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16 pages, 4433 KiB

Open AccessArticle

Genomic Epidemiology and Transmission Dynamics of Global Coxsackievirus B4

by Jinbo Xiao, Jianxing Wang, Huanhuan Lu, Yang Song, Dapeng Sun, Zhenzhi Han, Jichen Li, Qian Yang, Dongmei Yan, Shuangli Zhu, Yaowen Pei, Xianjun Wang, Wenbo Xu and Yong Zhang

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

Cited by 2 | Viewed by 1496

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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12 pages, 3276 KiB

Open AccessArticle

Coxsackievirus A6 Infection Causes Neurogenic Pathogenesis in a Neonatal Murine Model

by Qiang Sun, Jichen Li, Rui Wang, Tiantian Sun, Yanjun Zong, Congcong Wang, Ying Liu, Xiaoliang Li, Yang Song and Yong Zhang

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

Cited by 2 | Viewed by 1998

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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14 pages, 3474 KiB

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

by Jiratchaya Puenpa, Nutsada Saengdao, Nongkanok Khanarat, Sumeth Korkong, Jira Chansaenroj, Ritthideach Yorsaeng, Nasamon Wanlapakorn and Yong Poovorawan

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

Cited by 7 | Viewed by 2437

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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