Multi- #recombinant #Enterovirus A71 Subgenogroup C1 Isolates Associated with #Neurologic Disease, #France, 2016–2017 (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 6—June 2019 / Dispatch

Multirecombinant Enterovirus A71 Subgenogroup C1 Isolates Associated with Neurologic Disease, France, 2016–2017

Stéphanie Tomba Ngangas, Alexander Lukashev, Gwendoline Jugie, Olga Ivanova, Jean-Michel Mansuy, Catherine Mengelle, Jacques Izopet, Anne-Sophie L’honneur, Flore Rozenberg, David Leyssene, Denise Hecquet, Stéphanie Marque-Juillet, David Boutolleau, Sonia Burrel, Hélène Peigue-Lafeuille, Christine Archimbaud, Kimberley Benschop, Cécile Henquell, Audrey Mirand, and Jean-Luc Bailly

Author affiliations: Université Clermont Auvergne, Clermont-Ferrand, France (S. Tomba Ngangas, G. Jugie, H. Peigue-Lafeuille, C. Archimbaud, C. Henquell, A. Mirand, J.-L. Bailly); Sechenov University, Moscow, Russia (A. Lukashev); Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, Moscow (O. Ivanova); Centre Hospitalier Universitaire de Toulouse, Toulouse, France (J.-M. Mansuy, C. Mengelle, J. Izopet); Assistance Publique-Hôspitaux de Paris Cochin, Paris, France (A.-S. L’honneur, F. Rozenberg); Centre Hospitalier de la Côte Basque, Bayonne, France (D. Leyssene); Centre Hospitalier Universitaire Amiens, Amiens, France (D. Hecquet); Centre Hospitalier de Versailles, Le Chesnay, France (S. Marque-Juillet); Assistance Publique-Hôspitaux de Paris Pitié-Salpêtrière-Charles Foix, Paris (D. Boutolleau, S. Burrel); CHU Clermont-Ferrand, Clermont-Ferrand (H. Peigue-Lafeuille, C. Archimbaud, C. Henquell, A. Mirand, J.-L. Bailly); National Institute for Public Health and the Environment, Bilthoven, the Netherlands (K. Benschop)



In 2016, an upsurge of neurologic disease associated with infection with multirecombinant enterovirus A71 subgenogroup C1 lineage viruses was reported in France. These viruses emerged in the 2000s; 1 recombinant is widespread. This virus lineage has the potential to be associated with a long-term risk for severe disease among children.

Keywords: EV-A71; Encephalitis; Neurology; Pediatrics; France.



#Enterovirus A71 Phenotypes Causing #HFMD, #Vietnam (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 4—April 2019 / Dispatch

Enterovirus A71 Phenotypes Causing Hand, Foot and Mouth Disease, Vietnam

Hoang Minh Tu Van  , Nguyen To Anh, Nguyen Thi Thu Hong, Le Nguyen Truc Nhu, Lam Anh Nguyet, Tran Tan Thanh, Nguyen Thi Han Ny, Vu Thi Ty Hang, Truong Huu Khanh, Ho Lu Viet, Do Chau Viet, Ha Manh Tuan, Nguyen Thanh Hung, Du Tuan Quy, Do Quang Ha, Phan Tu Qui, Le Nguyen Thanh Nhan, Guy Thwaites, Nguyen Van Vinh Chau, Louise Thwaites, H. Rogier van Doorn, and Le Van Tan

Author affiliations: Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam (H.M.T. Van, N.T. Anh, N.T.T. Hong, L.N.T. Nhu, L.A. Nguyet, T.T. Thanh, N.T.H. Ny, V.T.T. Hang, D.Q. Ha, G. Thwaites, L. Thwaites, H.R. van Doorn, L.V. Tan); Children’s Hospital 2, Ho Chi Minh City (H.M.T. Van, H.L. Viet, D.C. Viet, H.M. Tuan); Children’s Hospital 1, Ho Chi Minh City (T.H. Khanh, N.T. Hung, D.T. Quy, L.N.T. Nhan); University of Oxford, Oxford, UK (P.T. Qui, G. Thwaites, L. Thwaites, H.R. van Doorn); Hospital for Tropical Diseases, Ho Chi Minh City (N.V.V. Chau)



We investigated enterovirus A71–associated hand, foot and mouth disease in Vietnam and found that, after replacing subgenogroup C4 in 2013, B5 remained the leading cause of this disease. In contrast with previous observations, this switch did not result in an explosive outbreak, and B5 evolution was driven by negative selection.

Keywords: Enterovirus; EV-A71; HFMD; Vietnam.


Polypyrimidine Tract-Binding #Protein Regulates #Enterovirus 71 #Translation Through Interaction with the Internal #Ribosomal Entry Site (Virol Sin., abstract)

[Source: Virologica Sinica, full page: (LINK). Abstract, edited.]

Polypyrimidine Tract-Binding Protein Regulates Enterovirus 71 Translation Through Interaction with the Internal Ribosomal Entry Site

Authors and affiliations: Juemin Xi 1, Fei Ye 2, Guanzhou Wang 2, Wei Han 2, Zhizhong Wei 2, Bin Yin 2, Jiangang Yuan 2, Boqin Qiang 2, Xiaozhong Peng 1, 2

1 Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China; 2 The State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Open Access / RESEARCH ARTICLE / First Online: 22 February 2019



Enterovirus 71 (EV71), a major causative agent of hand, foot, and mouth disease, has caused periodic infection outbreaks in children in the Asia–Pacific region. In order to describe the largely unknown life cycle of EV71, the molecular basis of its virus-host interactions must first be determined. The 5′ untranslated region of EV71 contains a cloverleaf-like structure and internal ribosomal entry site (IRES), which play an important role in transcription and translation of viral protein. We found that polypyrimidine tract-binding protein 1 (PTB) bound to the IRES of EV71. RNA recognition motifs 1 and 2 of PTB were responsible for its binding to the EV71 IRES. Moreover, PTB protein was shuttled from nucleus to cytoplasm after EV71 infection. Additionally, IRES activity and viral protein production were inhibited by PTB knockdown. These results suggest that PTB interacts with the EV71 IRES, and positively regulates viral protein translation.

Keywords: EV71 – IRES – PTB – Translation


Electronic supplementary material

The online version of this article ( contains supplementary material, which is available to authorized users.

Juemin Xi and Fei Ye contributed equally to this work.

Keywords: EV-71; HFMD.


#Surveillance of #enteroviruses from #paediatric patients attended at a tertiary #hospital in #Catalonia from 2014 to 2017 (J Clin Virol., abstract)

[Source: Science Direct, full page: (LINK). Abstract, edited.]

Journal of Clinical Virology / Available online 30 November 2018 / In Press, Accepted Manuscript

Surveillance of enteroviruses from paediatric patients attended at a tertiary hospital in Catalonia from 2014 to 2017

Cristina Andrés a, Jorgina Vila b, Laura Gimferrer a , Maria Piñana a, Juliana Esperalba a, Maria Gema Codina a, Meritxell Barnés b, Mariadel Carmen Martín a, Francisco Fuentes a, Susana Rubio a, Pilar Alcubilla a, Carlos Rodrigo b, Tomàs Pumarola a, Andrés Antón a

{a} Respiratory Viruses Unit, Virology Section, Microbiology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; {b} Paediatric Hospitalisation Unit, Department of Paediatrics, Hospital Universitari Maternoinfantil Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

Received 4 September 2018, Revised 26 October 2018, Accepted 16 November 2018, Available online 30 November 2018.




  • The study reports virological and clinical enterovirus surveillance in Catalonia.
  • The four enterovirus species cocirculated, distinguishing up to 27 different types.
  • Most of neurological studied cases were from the 2016 spring outbreak.
  • EV-A71 was one of the most detected EV, mostly during the outbreak.
  • Rhombencephalitis cases were related to EV-A71 infection.
  • EV-D68 was associated with lower respiratory tract infections.
  • Necessity to perform EV surveillance in primary care settings.




Enterovirus (EV) infections are usually asymptomatic or mild, but symptomatic infections can evolve to severe complications. Outbreaks of EV-A71 and EV-D68 have been recently reported worldwide, sometimes related to severe clinical outcomes.


To describe EV genetic diversity and the clinical outcomes from paediatric patients attended at a tertiary university hospital in Barcelona (Catalonia, Spain) from 2014 to 2017.

Study design

Specimens were collected from paediatric (<17 years old) cases with suspicion of respiratory tract infection or EV infection. EV laboratory-confirmation was performed by specific real-time multiplex RT-PCR assay. Partial viral VP1 protein was sequenced for genetic characterisation by phylogenetic analyses.


A total of 376 (7%) from 5,703 cases were EV laboratory-confirmed. Phylogenetic analyses of VP1 (210; 81%) sequences distinguished up to 27 different EV types distributed within EV-A (82; 40%), EV-B (90; 42%), EV-C (5; 2%), and EV-D (33; 15%), in addition to 50 (19%) rhinoviruses. The most predominant were EV-A71 (37; 45%) and EV-D68 (32; 99%). EV-A71 was highly related to neurological complications (25/39, 63%), of which 20/39 were rhombencephalitis, and most EV-D68 (28/32, 88%) were associated with lower respiratory tract infections (LRTI), and exceptionally one (3%) with flaccid paralysis.


EV-A71 and EV-D68 were the most detected EV in respiratory specimens. EV-A71 was highly related to neurological disease and EV-D68 was often associated with LRTI. However, both potential relatedness to neurological diseases makes the monitoring of EV circulation obligatory.

Keywords: enteroviruses – respiratory infections – surveillance – genetic diversity – molecular epidemiology – paediatric population

© 2018 Elsevier B.V. All rights reserved.

Keywords: Enterovirus; EV-A71; EV-D68; Rhomboencephalitis; AFP; Spain.


RSAD2 and AIM2 modulate CV-A16 and #EV-A71 #replication in #neuronal cells in different ways that may be associated with their 5′ non-translated regions (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

RSAD2 and AIM2 modulate CV-A16 and EV-A71 replication in neuronal cells in different ways that may be associated with their 5′ non-translated regions

Thinesshwary Yogarajah1,  Kien Chai Ong2,  David Perera3 and Kum Thong Wong1#

Author Affiliations: 1Departments of Pathology and 2Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 3Institute of Health and Community Medicine, Universiti Malaysia Sarawak, Sarawak, Malaysia.



Coxsackievirus A16 (CV-A16) and Enterovirus A71 (EV-A71) are closely related enteroviruses that cause the same hand, foot and mouth disease but neurological complications occur only very rarely in CV-A16 compared to EV-A71 infections. To elucidate host responses that may be able to explain these differences, we performed transcriptomic analysis and qRT-PCR in CV-A16 infected neuroblastoma cells (SK-N-SH) which showed that the radical s-adenosyl methionine domain containing 2 (RSAD2) was the highest up-regulated gene in the anti-microbial pathway. Increased RSAD2 expression was correlated with reduced viral replication while RSAD2 knockdown cells were correlated with increased replication. EV-A71 replication showed no apparent correlation to RSAD2 expressions. Absent in melanoma 2 (AIM2) which is associated with pyroptosis cell death was upregulated in EV-A71 infected neurons but not in CV-A16 infection, suggesting that the AIM2 inflammasome played a significant role in suppressing EV-A71 replication. Chimeric viruses derived from CV-A16 and EV-A71 but containing swapped 5′ non-translated regions (5′ NTR) showed that RSAD2 expression/viral replication and AIM2 expression/viral replication patterns may be linked to the 5′ NTRs of parental viruses. Differences in secondary structure of internal ribosomal entry sites within the 5′ NTR may be responsible for these findings. Overall, our results suggest that CV-A16 and EV-A71 elicit different host responses to infection, which may help explain the apparent lower incidence of CV-A16 associated neurovirulence in HFMD outbreaks compared to EV-A71 infection.



Although Coxsackievirus A16 (CV-A16) and Enterovirus A17 (EV-A71) both cause hand, foot and mouth disease, EV-A71 has emerged as a leading cause of non-polio, enteroviral fatal encephalomyelitis among young children. The significance of our research is in the identification of the possible differing and novel mechanisms of CV-A16 and EV-A71 inhibition in neuronal cells that may impact on viral neuropathogenesis. We further showed that viral 5′ NTRs may play significant roles in eliciting different host response mechanisms.

#Corresponding author: Kum Thong Wong,

Copyright © 2017 American Society for Microbiology. All Rights Reserved.

Keywords: EV-A71; Coxsackievirus A16; Encephalomyelitis; HFMD.


A selective #bottleneck shapes the evolutionary #mutant #spectra of #enterovirus A71 during viral dissemination in #humans (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

A selective bottleneck shapes the evolutionary mutant spectra of enterovirus A71 during viral dissemination in humans

Sheng-Wen Huang1, Yi-Hui Huang2, Huey-Pin Tsai2,3, Pin-Hwa Kuo3,Shih-Min Wang1,4, Ching-Chuan Liu1,5 and Jen-Ren Wang1,2,3,6*

Author Affiliations: 1 Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; 2 Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan; 3 Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan; 4 Department of Emergency Medicine, National Cheng Kung University, Tainan, Taiwan; 5 Department of Pediatrics, National Cheng Kung University, Tainan, Taiwan; 6 National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan



RNA viruses accumulate mutations to rapidly adapt to environmental changes. Enterovirus A71 (EV-A71) causes various clinical manifestations with occasional severe neurological complications. However, the mechanism by which EV-A71 evolves within the human body is unclear. Utilizing deep sequencing and haplotype analyses of viruses from various tissues of an autopsy patient, we sought to define the evolutionary pathway by which enterovirus A71 evolves fitness for invading the central nervous system in humans. Broad mutant spectra with divergent mutations were observed at the initial infection sites in the respiratory and digestive systems. After viral invasion, we identified a haplotype switch and dominant haplotype, with glycine at VP1 residue 31 in viral particles disseminated into the integumentary and central nervous systems. In vitro viral-growth and fitness analyses indicated that VP1-31G conferred growth and a fitness advantage in human neuronal cells, whereas VP1-31D showed enhanced replication in human colorectal cells. A higher proportion of VP1-31G was also found among fatal cases, suggesting that it may facilitate central nervous system infection in humans. Our data provide the first glimpse of EV-A71 quasispecies from oral tissues to central nervous system within humans, showing broad implications for the surveillance and pathogenesis of this re-emerging viral pathogen.



EV-A71 continues to be a worldwide burden to public health. Although EV-A71 is the major etiological agent of hand-foot-and-mouth disease, it can also cause neurological pulmonary edema, encephalitis, and even death, especially in children. Understanding selection processes enabling dissemination and accurately estimating EV-A71 diversity during invasion in humans are critical for applications in viral pathogenesis and vaccine studies. Here, we define a selection bottleneck appearing in respiratory and digestive tissues. Glycine substitution at VP1 residue 31 helps viruses break through the bottleneck and invade the central nervous system. This substitution is also advantageous for replication in neuronal cells in vitro. Considering that fatal cases contain enhanced glycine substitution at VP1-31, we suggest that the increased prevalence of VP1-31G may alter viral tropism and aid central nervous system invasion. Our findings provide new insights into a dynamic mutant spectral switch active during acute viral infection with emerging viral pathogens.



*Corresponding author: Prof. Jen-Ren Wang, Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, One University Road, Tainan, 701, Taiwan, Telephone: +886-6-2353535, Fax: +886-6-2760695, E-mail address:

Copyright © 2017 American Society for Microbiology. All Rights Reserved.

Keywords: EV-A71; Encephalitis; HFMD.


Co-circulation of multiple subtypes of #enterovirus A71 (EV- A71) genotype C, including novel #recombinants characterised by use of whole genome sequencing (WGS), #Denmark 2016 (@eurosurveillanc, abstract)

[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

Eurosurveillance, Volume 22, Issue 26, 29 June 2017  / Rapid communication

Co-circulation of multiple subtypes of enterovirus A71 (EV- A71) genotype C, including novel recombinants characterised by use of whole genome sequencing (WGS), Denmark 2016

SE Midgley 1 , AG Nielsen 1 , R Trebbien 1 , MW Poulsen 1 , PH Andersen 2 , TK Fischer 1 3

Author affiliations: 1. Section for Virus Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark; 2. Infectious Disease Epidemiology, Statens Serum Institut, Copenhagen, Denmark; 3. Center for Global Health, Department of Infectious Diseases, University of Southern Denmark, Odense, Denmark

Correspondence: Sofie Elisabeth Midgley (

Citation style for this article: Midgley SE, Nielsen AG, Trebbien R, Poulsen MW, Andersen PH, Fischer TK. Co-circulation of multiple subtypes of enterovirus A71 (EV- A71) genotype C, including novel recombinants characterised by use of whole genome sequencing (WGS), Denmark 2016. Euro Surveill. 2017;22(26):pii=30565. DOI:

Received:19 May 2017; Accepted:29 June 2017



In Europe, enterovirus A71 (EV-A71) has primarily been associated with sporadic cases of neurological disease. The recent emergence of new genotypes and larger outbreaks with severely ill patients demonstrates a potential for the spread of new, highly pathogenic EV-A71 strains. Detection and characterisation of these new emerging EV variants is challenging as standard EV assays may not be adequate, necessitating the use of whole genome analysis.

Keywords: EV-A71; Enterovirus; Denmark; HFMD; Acute Flaccid Paralysis.