scholarly journals Adaptation and Virulence of Enterovirus-A71

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1661
Author(s):  
Kyousuke Kobayashi ◽  
Satoshi Koike
Keyword(s):  
Foot And Mouth Disease ◽  
Asia Pacific ◽  
Health Concern ◽  
Virulence Determinants ◽  
Future Perspectives ◽  
Asia Pacific Region ◽  
Public Health Concern ◽  
Host Environment ◽  
Multiple Receptors ◽  
Enterovirus A71

Outbreaks of hand, foot, and mouth disease caused by enterovirus-A71 (EV-A71) can result in many deaths, due to central nervous system complications. Outbreaks with many fatalities have occurred sporadically in the Asia-Pacific region and have become a serious public health concern. It is hypothesized that virulent mutations in the EV-A71 genome cause these occasional outbreaks. Analysis of EV-A71 neurovirulence determinants is important, but there are no virulence determinants that are widely accepted among researchers. This is because most studies have been done in artificially infected mouse models and because EV-A71 mutates very quickly to adapt to the artificial host environment. Although EV-A71 uses multiple receptors for infection, it is clear that adaptation-related mutations alter the binding specificity of the receptors and allow the virus to adopt the best entry route for each environment. Such mutations have confused interpretations of virulence in animal models. This article will discuss how environment-adapted mutations in EV-A71 occur, how they affect virulence, and how such mutations can be avoided. We also discuss future perspectives for EV-A71 virulence research.

scholarly journals Enterovirus A71: virulence, antigenicity, and genetic evolution over the years

2019 ◽  
Vol 26 (1) ◽  
Author(s):  
Sheng-Wen Huang ◽  
Dayna Cheng ◽  
Jen-Ren Wang
Keyword(s):  
Neurological Disease ◽  
Foot And Mouth Disease ◽  
Asia Pacific ◽  
Pacific Region ◽  
Genetic Evolution ◽  
Virulence Determinants ◽  
Global Public Health ◽  
Asia Pacific Region ◽  
Enterovirus A71 ◽  
Global Epidemiology

Abstract As a neurotropic virus, enterovirus A71 (EV-A71) emerge and remerge in the Asia-Pacific region since the 1990s, and has continuously been a threat to global public health, especially in children. Annually, EV-A71 results in hand-foot-and-mouth disease (HFMD) and occasionally causes severe neurological disease. Here we reviewed the global epidemiology and genotypic evolution of EV-A71 since 1997. The natural selection, mutation and recombination events observed in the genetic evolution were described. In addition, we have updated the antigenicity and virulence determinants that are known to date. Understanding EV-A71 epidemiology, genetic evolution, antigenicity, and virulence determinants can expand our insights of EV-A71 pathogenesis, which may benefit us in the future.

Enterovirus Diseases and Vaccines

2021 ◽  
Author(s):  
Heinz-Josef Schmitt
Keyword(s):  
Disease Outbreaks ◽  
Foot And Mouth Disease ◽  
Asia Pacific ◽  
Asia Pacific Region ◽  
Internal Organs ◽  
Enterovirus A71 ◽  
Life Threatening ◽  
Development Pipeline ◽  
The Brain ◽  
Genus Enterovirus

Enterovirus A71 (EV A71) (genus enterovirus, family pircornaviridae) causes benign vesicular lesions on skin (hand, foot and mouth disease, HFMD) and mucous membranes of the mouth (herpangina), and also severe to life-threatening infections of the brain, the heart, and other internal organs. Disease outbreaks in the Asia-Pacific region regularly involve thousands of children <5 years resulting in many deaths. Such outbreaks are caused by specific EV genotypes that vary by time and place. While there are various promising and innovative options for treatment in development, none are licensed to date. Immunoglobulins may be beneficial through virus neutralization and modulation of the inflammatory response by the host. In China, 3 different highly efficacious and safe vaccines are commercially available; however, none are licensed outside the country. Roughly half a dozen vaccines are in the development pipeline, with some using innovative approaches and trying to broaden strain coverage.

scholarly journals Association of PM2.5 and its Components with Lengths of Hospital Stay for Hand Foot and Mouth Disease in Children

2021 ◽  
Author(s):  
Wei Li ◽  
Jieguo Wang ◽  
Kai Zhou ◽  
Ye Tian ◽  
Feiran Wei ◽  
...  
Keyword(s):  
Hospital Stay ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Health Concern ◽  
Public Health Concern ◽  
Short Term ◽  
Illness Onset ◽  
Short Term Exposure ◽  
Foot And Mouth ◽  
Demographic Features

Abstract Background Hand foot and mouth disease (HFMD) is a public health concern. Studies on air pollution and the lengths of hospital stay (LOS) of HFMD are scarce. Methods We characterized the clinic demographic features of 5135 hospitalized HFMD in Nanjing, China from 2012 to 2017, and analyzed the association between short-term exposure to PM2.5 as well as its components (OM, BC, SO42−, NH4+, NIT, SOIL and SS) and the LOS of HFMD. Results Among them 98.62% were aged 0–6 years old, and 3772 (73.46%) were hospitalized for seven days or less. The LOS of HFMD children was different in different ages, illness onset years and illness onset seasons (P<0.01). For per IQR increase in PM2.5 concentrations, LOS of HFMD increased by 0.52(0.33, 0.71), 0.50 (95% CI, 0.31–0.69) and 0.46 (95% CI, 0.28–0.65) day in adjusted models at lag 3 days, lag 7days and lag 14 days, respectively. In addition, per IQR increase of BC, SO42−, NH4+, NIT and SOIL were also significantly associated with the LOS of HFMD. Conclusions Our findings corroborated the hypothesis that short-term PM2.5 exposure was associated with increased the LOS of HFMD, and its components (BC, SO42−, NH4+, NIT and SOIL) of PM2.5 might play a key role in the prolonged LOS of HFMD.

scholarly journals Molecular epidemiology of an enterovirus A71 outbreak associated with severe neurological disease, Spain, 2016

2019 ◽  
Vol 24 (7) ◽  
Author(s):  
Rubén González-Sanz ◽  
Didac Casas-Alba ◽  
Cristian Launes ◽  
Carmen Muñoz-Almagro ◽  
María Montserrat Ruiz-García ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Phylogenetic Analyses ◽  
Clinical Manifestations ◽  
Foot And Mouth Disease ◽  
Neurological Complications ◽  
Asia Pacific ◽  
Enterovirus A71 ◽  
Hospitalised Patients ◽  
Wide Range ◽  
Large Outbreak

Introduction Enterovirus A71 (EV-A71) is an emerging pathogen that causes a wide range of disorders including severe neurological manifestations. In the past 20 years, this virus has been associated with large outbreaks of hand, foot and mouth disease with neurological complications in the Asia-Pacific region, while in Europe mainly sporadic cases have been reported. In spring 2016, however, an EV-A71 outbreak associated with severe neurological cases was reported in Catalonia and spread further to other Spanish regions. Aim Our objective was to investigate the epidemiology and clinical characteristics of the outbreak. Methods We carried out a retrospective study which included 233 EV-A71-positive samples collected during 2016 from hospitalised patients. We analysed the clinical manifestations associated with EV-A71 infections and performed phylogenetic analyses of the 3’-VP1 and 3Dpol regions from all Spanish strains and a set of EV-A71 from other countries. Results Most EV-A71 infections were reported in children (mean age: 2.6 years) and the highest incidence was between May and July 2016 (83%). Most isolates (218/233) were classified as subgenogroup C1 and 217 of them were grouped in one cluster phylogenetically related to a new recombinant variant strain associated with severe neurological diseases in Germany and France in 2015 and 2016. Moreover, we found a clear association of EV-A71-C1 infection with severe neurological disorders, brainstem encephalitis being the most commonly reported. Conclusion An emerging recombinant variant of EV-A71-C1 was responsible for the large outbreak in 2016 in Spain that was associated with many severe neurological cases.

Virulence of enterovirus-A71 fluctuates depending on the phylogenetic clade formed in the epidemic year and epidemic region

2021 ◽  
Author(s):  
Kyousuke Kobayashi ◽  
Hidekazu Nishimura ◽  
Katsumi Mizuta ◽  
Tomoha Nishizawa ◽  
Son T. Chu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Foot And Mouth Disease ◽  
Virus Genome ◽  
Mouth Disease ◽  
Asia Pacific ◽  
Enterovirus A71 ◽  
Viral Virulence ◽  
Foot And Mouth ◽  
Potential Risks ◽  
A Minor

Although epidemics of hand, foot, and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) have occurred worldwide, the Asia-Pacific region has seen large sporadic outbreaks with many severe neurological cases. This suggests that the virulence of the circulating viruses fluctuates in each epidemic and that HFMD outbreaks with many severe cases occur when highly virulent viruses are circulating predominantly, which has not been experimentally verified. Here, we analyzed 32 clinically isolated strains obtained in Japan from 2002 to 2013, along with 27 Vietnamese strains obtained from 2015 to 2016 that we characterized previously using human SCARB2 transgenic mice. Phylogenetic analysis of the P1 region classified them into five clades belonging to subgenogroup B5 (B5-I to B5-V) and five clades belonging to subgenogroup C4 (C4-I to C4-V) according to the epidemic year and region. Interestingly, the clade B5-I and B5-II were very virulent, while clades B5-III, B5-IV, and B5-V were less virulent. Clades C4-II, C4-III, C4-IV, and C4-V were virulent, while clade C4-I was not. The result experimentally showed for the first time that several clades with different virulence levels emerged one after another. The experimental virulence evaluation of circulating viruses using SCARB2 transgenic mice is helpful to assess potential risks of circulating viruses. These results also suggest that a minor nucleotide or amino acid substitution in the EV-A71 genome during circulation may cause fluctuations in virulence. The data presented herein may increase our understanding of the dynamics of viral virulence during epidemics. IMPORTANCE Outbreaks of hand, foot, and mouth disease (HFMD) with severe enterovirus A71 (EV-A71) cases have occurred repeatedly, mainly in Asia. In severe cases, central nervous system complications can lead to death, making it an infectious disease of importance to public health. An unanswered question about this disease is why outbreaks of HFMD with many severe cases sometimes occur. Here, we collected EV-A71 strains that were prevalent in Japan and Vietnam over the past 20 years and evaluated their virulence in a mouse model of EV-A71 infection. This method clearly revealed that viruses belonging to different clades have different virulence, indicating that the method is powerful to assess the potential risks of the circulating viruses. The results also suggested that factors in the virus genome may potentially cause an outbreak with many severe cases and that further studies may facilitate the prediction of large epidemics of EV-A71 in the future.

scholarly journals Phylogenetic Analysis of Enterovirus 71 Strains Isolated during Linked Epidemics in Malaysia, Singapore, and Western Australia

2001 ◽  
Vol 75 (16) ◽  
pp. 7732-7738 ◽  
Author(s):  
Peter McMinn ◽  
Katie Lindsay ◽  
David Perera ◽  
Hung Ming Chan ◽  
Kwai Peng Chan ◽  
...  
Keyword(s):  
Western Australia ◽  
Enterovirus 71 ◽  
Case Fatality ◽  
Foot And Mouth Disease ◽  
Severe Form ◽  
Asia Pacific ◽  
Pacific Region ◽  
Asia Pacific Region ◽  
Neurological Sequelae ◽  
Genetic Lineages

ABSTRACT Enterovirus 71 (EV71) is a frequent cause of hand, foot, and mouth disease (HFMD) epidemics associated with severe neurological sequelae in a small proportion of cases. There has been a significant increase in EV71 epidemic activity throughout the Asia-Pacific region since 1997. Recent HFMD epidemics in this region have been associated with a severe form of brainstem encephalitis associated with pulmonary edema and high case fatality rates. In this study, we show that four genetic lineages of EV71 have been prevalent in the Asia-Pacific region since 1997, including two previously undescribed genogroups (B3 and B4). Furthermore, we show that viruses belonging to genogroups B3 and B4 have circulated endemically in Southeast Asia during this period and have been the primary cause of several large HFMD or encephalitis epidemics in Malaysia, Singapore, and Western Australia.

scholarly journals A novel attenuated enterovirus A71 mutant with VP1-V238A,K244R exhibits reduced efficiency of cell entry/exit and augmented binding affinity to sulfated glycans

2021 ◽  
Author(s):  
Tao Meng ◽  
Sek-Man Wong ◽  
Kaw-Bing Chua
Keyword(s):  
Binding Affinity ◽  
Neutralizing Antibodies ◽  
Lethal Dose ◽  
Vero Cells ◽  
Cell Entry ◽  
Asia Pacific ◽  
Virulence Determinants ◽  
Food Dye ◽  
Enterovirus A71

Enterovirus A71 (EV-A71) is one of the major etiological agents of hand, foot, and mouth disease, and its infection occasionally leads to fatal neurological complications in children. However, only inactivated whole virus vaccines against EV-A71 are commercially available in Mainland China. Furthermore, the mechanisms underlying the infectivity and pathogenesis of EV-A71 remain to be better understood. By adaptation of an EV-A71 B5 strain in monkey Vero cells in the presence of brilliant black BN (E151), an anti-EV-A71 agent, a double mutant with VP1-V238A,K244R emerged to be E151 enhanced infection. The growth of reverse genetics (RG) mutant RG/B5-VP1-V238A,K244R (RG/B5-AR) was promoted by E151 in Vero cells, but inhibited in other human and murine cells; while its parental wild type RG/B5-wt was strongly prevented by E151 from infection in all tested cells. In the absence of E151, RG/B5-AR exhibited defective cell entry/exit, resulting in reduced viral transmission and growth in vitro . It had augmented binding affinity to sulfated glycans, cells and tissue/organs, which probably functioned as decoys to restrict viral dissemination and infection. RG/B5-AR was also attenuated with 355 times higher 50% lethal dose and shorter timing of virus clearance than RG/B5-wt in suckling AG129 mice. It, however, remained highly immunogenic in adult AG129 mice to protect their suckling mice from lethal EV-A71 challenges through maternal neutralizing antibodies. Overall, discovery of the attenuated mutant RG/B5-AR contributes to better understanding of virulence determinants of EV-A71 and further development of novel vaccines against EV-A71. Importance Enterovirus A71 (EV-A71) is highly contagious in children and has been responsible for thousands of deaths in Asia-Pacific region since 1990s. Unfortunately, the virulence determinants and pathogenesis of EV-A71 are not fully clear. We discovered that a novel EV-A71 mutant VP1-V238A,K244R showed growth attenuation with reduced efficiency of cell entry/exit. In Vero cell line which has been approved for manufacturing EV-A71 vaccines, the growth defects of the mutant were compensated by a food dye brilliant black BN. The mutant was also with augmented binding affinity to sulfated glycans and other cellular components which probably restricted the viral infection and dissemination. Therefore, it was virulence attenuated in a mouse model but still retained its immunogenicity. Our findings suggest the mutant as a promising vaccine candidate against EV-A71 infection.

scholarly journals Association of PM2.5 and Its Components With Lengths of Hospital Stay for Hand Foot and Mouth Disease in Children

2021 ◽  
Author(s):  
Wei Li ◽  
Jieguo Wang ◽  
Kai Zhou ◽  
Ye Tian ◽  
Feiran Wei ◽  
...  
Keyword(s):  
Hospital Stay ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Health Concern ◽  
Public Health Concern ◽  
Short Term ◽  
Illness Onset ◽  
Short Term Exposure ◽  
Foot And Mouth ◽  
Demographic Features

Abstract Background Hand foot and mouth disease (HFMD) is a public health concern. Studies on air pollution and the lengths of hospital stay (LOS) of HFMD are scarce. Methods We characterized the clinic demographic features of 5135 hospitalized HFMD in Nanjing, China from 2012 to 2017, and analyzed the association between short-term exposure to PM2.5 as well as its components (OM, BC, SO42−, NH4+, NIT, SOIL and SS) and the LOS of HFMD. Results Among them 98.62% were aged 0–6 years old, and 3772 (73.46%) were hospitalized for seven days or less. The LOS of HFMD children was different in different ages, illness onset years and illness onset seasons (P<0.01). For per IQR increase in PM2.5 concentrations, LOS of HFMD increased by 0.52(0.33, 0.71), 0.50 (95% CI, 0.31–0.69) and 0.46 (95% CI, 0.28–0.65) day in adjusted models at lag 3 days, lag 7days and lag 14 days, respectively. In addition, per IQR increase of BC, SO42−, NH4+, NIT and SOIL were also significantly associated with the LOS of HFMD. Conclusions Our findings corroborated the hypothesis that short-term PM2.5 exposure was associated with increased the LOS of HFMD, and its components (BC, SO42−, NH4+, NIT and SOIL) of PM2.5 might play a key role in the prolonged LOS of HFMD.

scholarly journals Dysregulated autophagy contributes to the pathogenesis of enterovirus A71 infection

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Chuanjie Zhang ◽  
Yawei Li ◽  
Jingfeng Li
Keyword(s):  
Foot And Mouth Disease ◽  
Epidemiological Studies ◽  
Asia Pacific ◽  
Global Public Health ◽  
Viral Spread ◽  
Autophagy Induction ◽  
Viral Therapy ◽  
Enterovirus A71 ◽  
Promising Therapeutic Target ◽  
Fundamental Research

AbstractEnterovirus A71 (EVA71) infection continues to remain a vital threat to global public health, especially in the Asia–Pacific region. It is one of the most predominant pathogens that cause hand, foot, and mouth disease (HFMD), which occurs mainly in children below 5 years old. Although EVA71 prevalence has decreased sharply in China with the use of vaccines, epidemiological studies still indicate that EVA71 infection involves severe and even fatal HFMD cases. As a result, it remains more fundamental research into the pathogenesis of EVA71 as well as to develop specific anti-viral therapy. Autophagy is a conserved, self-degradation system that is critical for maintaining cellular homeostasis. It involves a variety of biological functions, such as development, cellular differentiation, nutritional starvation, and defense against pathogens. However, accumulating evidence has indicated that EVA71 induces autophagy and hijacks the process of autophagy for their optimal infection during the different stages of life cycle. This review provides a perspective on the emerging evidence that the “positive feedback” between autophagy induction and EVA71 infection, as well as its potential mechanisms. Furthermore, autophagy may be involved in EVA71-induced nervous system impairment through mediating intracranial viral spread and dysregulating host regulator involved self-damage. Autophagy is a promising therapeutic target in EVA71 infection.

scholarly journals Susceptibility and cytokine responses of human neuronal cells to multiple circulating EV-A71 genotypes in India

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Madhu Chhanda Mohanty ◽  
Swapnil Yashavant Varose ◽  
Vinay Kumar Saxena
Keyword(s):  
Inflammatory Cytokines ◽  
Neuronal Cells ◽  
Foot And Mouth Disease ◽  
Asia Pacific ◽  
Delayed Response ◽  
Cytokine Responses ◽  
Enterovirus A71 ◽  
Infected Cells ◽  
Human Neuronal Cells

AbstractEnterovirus-A71 (EV-A71) associated Hand, foot and mouth disease (HFMD) is a highly contagious viral infection affecting children in Asia–Pacific region and has become a major threat to public health. Although several EV-A71 genotypes (C, D, and G) were isolated in India in recent years, no recognizable outbreak of EV-A71 caused HFMD, Acute Flaccid paralysis (AFP) or encephalitis have been reported so far. It is essential to study the pathogenicity or cell tropism of these Indian isolates in order to understand their tendency to cause disease. We investigated the susceptibility and cytokine responses of indigenous EV-A71 genotypes (D and G) isolated from cases of AFP and genotype C viruses isolated from cases of HFMD and encephalitis, in human cells in-vitro. Although all three EV-A71 genotypes could infect and replicate in human muscle and neuronal cells, the genotype D virus showed a delayed response in human neuronal cells. Quantification of cytokine secretion in response to these isolates followed by confirmation with gene expression assays in human neuronal cells revealed significantly higher secretion of pro-inflammatory cytokines TNF-α IL-8, IL-6, IP-10 (p < 0.001) in G genotype infected cells as compared to pathogenic C genotypes whereas the genotype D virus could not induce any of the inflammatory cytokines. These findings will help to better understand the host response to indigenous EV-A71 genotypes for management of future EV-A71 outbreaks in India, if any.

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