Special Issue "Enteroviruses"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (31 March 2019).

Special Issue Editor

Dr. Xiao-Fang Yu
E-Mail Website
Guest Editor
W. Harry Feinstone Department, Molecular Microbiology & Immunology, Johns Hopkins University, Bloomberg School of Public Health, 615 N Wolfe St., Room E5148, Baltimore, MD 21205, USA
Interests: HIV; HBV; host restriction; innate immunity; vaccine; ubiquitin

Special Issue Information

Dear Colleagues,

The genus Enterovirus is comprised of a unique group of RNA viruses within the Picornaviridae family, including enterovirus, coxsackievirus, poliovirus, echovirus, and rhinovirus, which are causative agents of the widest spectrum of severe and deadly diseases (aseptic meningitis, neonatal sepsis- like disease, encephalitis, acute flaccid paralysis (AFP), non- specificfebrile illness, hand- foot- and- mouth disease (HFMD), herpangina, pleurodynia, pericarditis, and myocarditis) of higher vertebrates, including humans. To date, there are no effective prophylactics or therapeutic treatments available for the treatment of enterovirus diseases. The significance of enterovirus in human health, together with the limited existing intervesion strategies to combat enterovirus infection, makes it extremely urgent to better understand the biology of these viruses and to develop effective countermeasures to prevent them from infecting humans. The goal of this Special Issue is to provide a firm base for the most recent discoveries in enterovirus research, including the molecular and structural biology of the virus, virus–host interactions, viral pathogenesis, antiviral strategies, and vaccine development.

Dr. Xiao-Fang Yu
Guest Editor

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Keywords

  • Enterovirus
  • Coxsackievirus
  • Poliovirus
  • Echovirus
  • Rhinovirus
  • Hand-foot and-mouth disease
  • HFMD

Published Papers (11 papers)

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Research

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Article
Identification and Phylogenetic Characterization of Human Enteroviruses Isolated from Cases of Aseptic Meningitis in Brazil, 2013–2017
Viruses 2019, 11(8), 690; https://doi.org/10.3390/v11080690 - 29 Jul 2019
Cited by 12 | Viewed by 1373
Abstract
Aseptic meningitis is a common viral infection associated with human enteroviruses. The aim of the present study was to identify and characterize the enteroviruses associated with outbreaks and sporadic cases of aseptic meningitis that occurred in different regions of Brazil between 2013 and [...] Read more.
Aseptic meningitis is a common viral infection associated with human enteroviruses. The aim of the present study was to identify and characterize the enteroviruses associated with outbreaks and sporadic cases of aseptic meningitis that occurred in different regions of Brazil between 2013 and 2017. Cerebrospinal fluids obtained from patients admitted to public health facilities were analyzed. A total of 303 patients were positive for Human Enteroviruses (EV) by cell culture isolation with a median isolation rate throughout the year of 12%. We were able to identify enterovirus serotypes in 295 clinical specimens. Nineteen different serotypes were identified; the large majority corresponded to HEV-B species. Echovirus 30 (E-30) and Echovirus 6 (E-6) were the most prevalent genotypes (66.8%). Sequence analysis suggested that circulating E-30 was closely related to E-30 from other American countries; while E-6 was derived from Europe. Most of the patients consisted of children ≤ 15 years old. The temporal distribution of all aseptic meningitis and EV-positive cases showed an obvious seasonal pattern during autumn. Our results have provided valuable information about the enteroviral etiology of the aseptic meningitis cases in Brazil pointing to the importance of enterovirus surveillance in neurological diseases. Full article
(This article belongs to the Special Issue Enteroviruses)
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Article
The Mechanism of Onychomadesis (Nail Shedding) and Beau’s Lines Following Hand-Foot-Mouth Disease
Viruses 2019, 11(6), 522; https://doi.org/10.3390/v11060522 - 06 Jun 2019
Cited by 2 | Viewed by 1812
Abstract
Background: Nail changes, including onychomadesis (nail shedding) and Beau’s line, following hand-foot-mouth disease (HFMD) are a common emergence at the stage of late complications of HFMD. However, the exact mechanism is still unknown. Therefore, we conducted this study to elucidate the mechanism of [...] Read more.
Background: Nail changes, including onychomadesis (nail shedding) and Beau’s line, following hand-foot-mouth disease (HFMD) are a common emergence at the stage of late complications of HFMD. However, the exact mechanism is still unknown. Therefore, we conducted this study to elucidate the mechanism of nail changes following HFMD. Methods: We collected 11 patients suffering from onychomadesis following HFMD. Nail samples from all of them were collected. Real time reverse transcription polymerase chain reaction (RT-PCR) and sequencing for human enteroviruses (HEV) were performed. Throat swabs for RT-PCR and sequencing for HEV were performed for three cases. Results: RT-PCR demonstrated the presence of Coxackievirus A6 (CVA6) in nail samples from three patients and one with Echovirus. Conclusion: In conclusion, we believe that the major cause of onychomadesis following HFMD is that certain novel viruses, mostly CVA6, are virulent and may damage nail matrix. Direct injury caused by cutaneous lesions of HFMD around nail matrix is a minor cause. There are still other virulent HEV which may result in onychomadesis. In addition, the novel strain of CVA6 also causes atypical clinical presentations, such as adult involvement and delayed-onset palmar and plantar desquamation. Physicians should be familiar with atypical presentations caused by novel viruses to avoid misdiagnosis and even inform patients of the possibility of onychomadesis that may take place weeks later to reassure patients. Full article
(This article belongs to the Special Issue Enteroviruses)
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Article
Enterovirus A71 VP1 Variation A289T Decreases the Central Nervous System Infectivity via Attenuation of Interactions between VP1 and Vimentin In Vitro and In Vivo
Viruses 2019, 11(5), 467; https://doi.org/10.3390/v11050467 - 22 May 2019
Cited by 6 | Viewed by 1305
Abstract
Vimentin (VIM) is a surface receptor for enterovirus-A71, mediating the initial binding and subsequent increase in EV-A71 infectivity. The caspid protein VP1 variation, A289T, is reportedly closely associated with less severe central nervous system (CNS) infections in humans. However, it is unclear whether [...] Read more.
Vimentin (VIM) is a surface receptor for enterovirus-A71, mediating the initial binding and subsequent increase in EV-A71 infectivity. The caspid protein VP1 variation, A289T, is reportedly closely associated with less severe central nervous system (CNS) infections in humans. However, it is unclear whether VIM is associated with a reduction in CNS infections of EV-A71 in the presence of A289T. We investigated whether VIM served as a receptor for EV-A71 in the presence of an A298T substitution in VP1. EV-A71-289A and EV-A71-289T were used to infect human rhabdomyosarcoma cells, control human brain microvascular endothelial cells (HBMECs), and VIM-knockout (KO) HBMECs and inoculated BALB/c mice, SV129 mice, and VIM-KO SV129 mice. Furthermore, we cloned VP1-289A-Flag and VP1-289T-Flag proteins for co-immunoprecipitation analysis. Analysis of viral function revealed that the capacity of viral attachment, replication, and protein synthesis and secretion decreased in HBMECs during an EV-A71-289A infection, the infectivity being higher than that of EV-A71-289T upon VIM-KO. Histopathological and immunohistochemical analyses of brain tissue revealed that cerebral cortical damage was more extensive in EV-A71-289A than in EV-A71-289T infections in control SV129 mice; however, no significant difference was observed upon VIM-KO. Co-immunoprecipitation analysis revealed an interaction between VP1 and VIM, which was attenuated in VP1 harboring A289T; however, this attenuation was reversed by VIM (1-58) peptide. The A289T variation of VP1 specifically decreased the virulence of EV-A71 in HBMECs, and the attenuated interaction between VP1 harboring the A289T variation and VIM essentially decreased the CNS infectivity of EV-A71 in vitro and vivo. Full article
(This article belongs to the Special Issue Enteroviruses)
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Article
Environmental Surveillance for Poliovirus and Other Enteroviruses: Long-Term Experience in Moscow, Russian Federation, 2004–2017
Viruses 2019, 11(5), 424; https://doi.org/10.3390/v11050424 - 08 May 2019
Cited by 14 | Viewed by 1722
Abstract
Polio and enterovirus surveillance may include a number of approaches, including incidence-based observation, a sentinel physician system, environmental monitoring and acute flaccid paralysis (AFP) surveillance. The relative value of these methods is widely debated. Here we summarized the results of 14 years of [...] Read more.
Polio and enterovirus surveillance may include a number of approaches, including incidence-based observation, a sentinel physician system, environmental monitoring and acute flaccid paralysis (AFP) surveillance. The relative value of these methods is widely debated. Here we summarized the results of 14 years of environmental surveillance at four sewage treatment plants of various capacities in Moscow, Russia. A total of 5450 samples were screened, yielding 1089 (20.0%) positive samples. There were 1168 viruses isolated including types 1–3 polioviruses (43%) and 29 different types of non-polio enteroviruses (51%). Despite using the same methodology, a significant variation in detection rates was observed between the treatment plants and within the same facility over time. The number of poliovirus isolates obtained from sewage was roughly 60 times higher than from AFP surveillance over the same time frame. All except one poliovirus isolate were Sabin-like polioviruses. The one isolate was vaccine-derived poliovirus type 2 with 17.6% difference from the corresponding Sabin strain, suggesting long-term circulation outside the scope of the surveillance. For some non-polio enterovirus types (e.g., Echovirus 6) there was a good correlation between detection in sewage and incidence of clinical cases in a given year, while other types (e.g., Echovirus 30) could cause large outbreaks and be almost absent in sewage samples. Therefore, sewage monitoring can be an important part of enterovirus surveillance, but cannot substitute other approaches. Full article
(This article belongs to the Special Issue Enteroviruses)
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Article
Propagation of Rhinovirus C in Differentiated Immortalized Human Airway HBEC3-KT Epithelial Cells
Viruses 2019, 11(3), 216; https://doi.org/10.3390/v11030216 - 04 Mar 2019
Cited by 3 | Viewed by 1914
Abstract
Rhinoviruses (RVs) are classified into three species: RV-A, B, and C. Unlike RV-A and -B, RV-C cannot be propagated using standard cell culture systems. In order to isolate RV-Cs from clinical specimens and gain a better understanding of their biological properties and pathogenesis, [...] Read more.
Rhinoviruses (RVs) are classified into three species: RV-A, B, and C. Unlike RV-A and -B, RV-C cannot be propagated using standard cell culture systems. In order to isolate RV-Cs from clinical specimens and gain a better understanding of their biological properties and pathogenesis, we established air–liquid-interface (ALI) culture methods using HBEC3-KT and HSAEC1-KT immortalized human airway epithelial cells. HBEC3- and HSAEC1-ALI cultures morphologically resembled pseudostratified epithelia with cilia and goblet cells. Two fully sequenced clinical RV-C isolates, RV-C9 and -C53, were propagated in HBEC3-ALI cultures, and increases in viral RNA ranging from 1.71 log10 to 7.06 log10 copies were observed. However, this propagation did not occur in HSAEC1-ALI cultures. Using the HBEC3-ALI culture system, 11 clinical strains of RV-C were isolated from 23 clinical specimens, and of them, nine were passaged and re-propagated. The 11 clinical isolates were classified as RV-C2, -C6, -C9, -C12, -C18, -C23, -C40, and -C53 types according to their VP1 sequences. Our stable HBEC3-ALI culture system is the first cultivable cell model that supports the growth of multiple RV-C virus types from clinical specimens. Thus, the HBEC3-ALI culture system provides a cheap and easy-to-use alternative to existing cell models for isolating and investigating RV-Cs. Full article
(This article belongs to the Special Issue Enteroviruses)
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Article
Staufen1 Protein Participates Positively in the Viral RNA Replication of Enterovirus 71
Viruses 2019, 11(2), 142; https://doi.org/10.3390/v11020142 - 08 Feb 2019
Cited by 4 | Viewed by 1672
Abstract
The double-stranded RNA-binding protein Staufen1 (Stau1) has multiple functions during RNA virus infection. In this study, we investigated the role of Stau1 in viral translation by using a combination of enterovirus 71 (EV-A71) infection, RNA reporter transfection, and in vitro functional and biochemical [...] Read more.
The double-stranded RNA-binding protein Staufen1 (Stau1) has multiple functions during RNA virus infection. In this study, we investigated the role of Stau1 in viral translation by using a combination of enterovirus 71 (EV-A71) infection, RNA reporter transfection, and in vitro functional and biochemical assays. We demonstrated that Stau1 specifically binds to the 5′-untranslated region of EV-A71 viral RNA. The RNA-binding domain 2-3 of Stau1 is responsible for this binding ability. Subsequently, we created a Stau1 knockout cell line using the CRISPR/Cas9 approach to further characterize the functional role of Stau1’s interaction with viral RNA in the EV-A71-infected cells. Both the viral RNA accumulation and viral protein expression were downregulated in the Stau1 knockout cells compared with the wild-type naïve cells. Moreover, dysregulation of viral RNA translation was observed in the Stau1 knockout cells using ribosome fractionation assay, and a reduced RNA stability of 5′-UTR of the EV-A71 was also identified using an RNA stability assay, which indicated that Stau1 has a role in facilitating viral translation during EV-A71 infection. In conclusion, we determined the functional relevance of Stau1 in the EV-A71 infection cycle and herein describe the mechanism of Stau1 participation in viral RNA translation through its interaction with viral RNA. Our results suggest that Stau1 is an important host factor involved in viral translation and influential early in the EV-A71 replication cycle. Full article
(This article belongs to the Special Issue Enteroviruses)
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Article
Viperin Inhibits Enterovirus A71 Replication by Interacting with Viral 2C Protein
Viruses 2019, 11(1), 13; https://doi.org/10.3390/v11010013 - 26 Dec 2018
Cited by 11 | Viewed by 2066
Abstract
Enterovirus A71 (EVA71) is a human enterovirus belonging to the Picornaviridae family and mostly causes hand-foot-and-mouth disease in infants. Viperin is an important interferon-stimulated gene with a broad antiviral activity against various viruses. However, the effect of viperin on human enteroviruses and the [...] Read more.
Enterovirus A71 (EVA71) is a human enterovirus belonging to the Picornaviridae family and mostly causes hand-foot-and-mouth disease in infants. Viperin is an important interferon-stimulated gene with a broad antiviral activity against various viruses. However, the effect of viperin on human enteroviruses and the interaction mechanism between EVA71 and viperin remains elusive. Here, we confirmed the EVA71-induced expression of viperin in a mouse model and cell lines and showed that viperin upregulation by EVA71 infection occurred on both the mRNA and protein level. Viperin knockdown and overexpression in EVA71-infected cells indicated that this protein can markedly inhibit EVA71 infection. Interestingly, immunofluorescent confocal microscopy and co-immunoprecipitation assays indicated that viperin interacts and colocalizes with the EVA71 protein 2C in the endoplasmic reticulum. Furthermore, amino acids 50–60 in the N-terminal domain of viperin were the key residues responsible for viperin interaction with 2C. More importantly, the N-terminal domain of viperin was found responsible for inhibiting EVA71 replication. Our findings can potentially aid future research on the prevention and treatment of nervous system damage caused by EVA71 and may provide a potential target for antiviral therapy. Full article
(This article belongs to the Special Issue Enteroviruses)
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Article
Toll-Like Receptor 3 Is Involved in Detection of Enterovirus A71 Infection and Targeted by Viral 2A Protease
Viruses 2018, 10(12), 689; https://doi.org/10.3390/v10120689 - 05 Dec 2018
Cited by 8 | Viewed by 1844
Abstract
Enterovirus A71 (EV-A71) has emerged as a major pathogen causing hand, foot, and mouth disease, as well as neurological disorders. The host immune response affects the outcomes of EV-A71 infection, leading to either resolution or disease progression. However, the mechanisms of how the [...] Read more.
Enterovirus A71 (EV-A71) has emerged as a major pathogen causing hand, foot, and mouth disease, as well as neurological disorders. The host immune response affects the outcomes of EV-A71 infection, leading to either resolution or disease progression. However, the mechanisms of how the mammalian innate immune system detects EV-A71 infection to elicit antiviral immunity remain elusive. Here, we report that the Toll-like receptor 3 (TLR3) is a key viral RNA sensor for sensing EV-A71 infection to trigger antiviral immunity. Expression of TLR3 in HEK293 cells enabled the cells to sense EV-A71 infection, leading to type I, IFN-mediated antiviral immunity. Viral double-stranded RNA derived from EV-A71 infection was a key ligand for TLR3 detection. Silencing of TLR3 in mouse and human primary immune cells impaired the activation of IFN-β upon EV-A71 infection, thus reinforcing the importance of the TLR3 pathway in defending against EV-A71 infection. Our results further demonstrated that TLR3 was a target of EV-A71 infection. EV-A71 protease 2A was implicated in the downregulation of TLR3. Together, our results not only demonstrate the importance of the TLR3 pathway in response to EV-A71 infection, but also reveal the involvement of EV-A71 protease 2A in subverting TLR3-mediated antiviral defenses. Full article
(This article belongs to the Special Issue Enteroviruses)
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Review

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Review
Impact of Rhinovirus Infections in Children
Viruses 2019, 11(6), 521; https://doi.org/10.3390/v11060521 - 05 Jun 2019
Cited by 16 | Viewed by 2502
Abstract
Rhinovirus (RV) is an RNA virus that causes more than 50% of upper respiratory tract infections in humans worldwide. Together with Respiratory Syncytial Virus, RV is one of the leading causes of viral bronchiolitis in infants and the most common virus associated with [...] Read more.
Rhinovirus (RV) is an RNA virus that causes more than 50% of upper respiratory tract infections in humans worldwide. Together with Respiratory Syncytial Virus, RV is one of the leading causes of viral bronchiolitis in infants and the most common virus associated with wheezing in children aged between one and two years. Because of its tremendous genetic diversity (>150 serotypes), the recurrence of RV infections each year is quite typical. Furthermore, because of its broad clinical spectrum, the clinical variability as well as the pathogenesis of RV infection are nowadays the subjects of an in-depth examination and have been the subject of several studies in the literature. In fact, the virus is responsible for direct cell cytotoxicity in only a small way, and it is now clearer than ever that it may act indirectly by triggering the release of active mediators by structural and inflammatory airway cells, causing the onset and/or the acute exacerbation of asthmatic events in predisposed children. In the present review, we aim to summarize the RV infection’s epidemiology, pathogenetic hypotheses, and available treatment options as well as its correlation with respiratory morbidity and mortality in the pediatric population. Full article
(This article belongs to the Special Issue Enteroviruses)
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Review
Current Understanding of Human Enterovirus D68
Viruses 2019, 11(6), 490; https://doi.org/10.3390/v11060490 - 29 May 2019
Cited by 23 | Viewed by 2513
Abstract
Human enterovirus D68 (EV-D68), a member of the species Enterovirus D of the Picornaviridae family, was first isolated in 1962 in the United States. EV-D68 infection was only infrequently reported until an outbreak occurred in 2014 in the US; since then, it has [...] Read more.
Human enterovirus D68 (EV-D68), a member of the species Enterovirus D of the Picornaviridae family, was first isolated in 1962 in the United States. EV-D68 infection was only infrequently reported until an outbreak occurred in 2014 in the US; since then, it has continued to increase worldwide. EV-D68 infection leads to severe respiratory illness and has recently been reported to be linked to the development of the neurogenic disease known as acute flaccid myelitis (AFM), mostly in children, seriously endangering public health. Hitherto, treatment options for EV-D68 infections were limited to supportive care, and as yet there are no approved, specific antiviral drugs or vaccines. Research on EV-D68 has mainly focused on its epidemiology, and its virologic characteristics and pathogenesis still need to be further explored. Here, we provide an overview of current research on EV-D68, including the genotypes and genetic characteristics of recent epidemics, the mechanism of infection and virus–host interactions, and its relationship to acute flaccid myelitis (AFM), in order to broaden our understanding of the biological features of EV-D68 and provide a basis for the development of effective antiviral agents. Full article
(This article belongs to the Special Issue Enteroviruses)
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Other

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Brief Report
Detection and Characterization of Enterovirus B73 from a Child in Brazil
Viruses 2019, 11(1), 16; https://doi.org/10.3390/v11010016 - 28 Dec 2018
Cited by 9 | Viewed by 1690
Abstract
Enterovirus B73 is a new member of the Enterovirus B species. First detected in the USA, it has been subsequently identified in China, India, Oman, and the Netherlands. In this study, we characterize the first B73 strain (named TO-127) to be detected in [...] Read more.
Enterovirus B73 is a new member of the Enterovirus B species. First detected in the USA, it has been subsequently identified in China, India, Oman, and the Netherlands. In this study, we characterize the first B73 strain (named TO-127) to be detected in South America. TO-127 was obtained from a child with acute gastroenteritis living in a rural area in Northern Brazil. The subject was not infected with any known enteric pathogens such as norovirus, rotavirus, helminths, or enteric bacteria. Analysis of the nearly full-length TO-127 genome (6993 nt) indicated a 74–75% nucleotide similarity with EV-B73 strains from other countries. Evolutionary analysis suggests that B73 is endemic and widespread. Full article
(This article belongs to the Special Issue Enteroviruses)
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