Enterovirus pathogenesis requires the host methyltransferase SETD3.

Animals CRISPR-Cas Systems Central Nervous System Viral Diseases / virology Disease Models, Animal Encephalitis, Viral Enterovirus / genetics Enterovirus Infections / virology Histone Methyltransferases / genetics Methyltransferases / metabolism Mice Myelitis / virology Neuromuscular Diseases / virology Proteolysis Viral Proteins Virus Replication

Journal

Nature microbiology
ISSN: 2058-5276
Titre abrégé: Nat Microbiol
Pays: England
ID NLM: 101674869

Informations de publication

Date de publication:
12 2019
Historique:
received: 11 03 2019
accepted: 26 07 2019
pubmed: 19 9 2019
medline: 1 7 2020
entrez: 19 9 2019
Statut: ppublish

Résumé

Enteroviruses (EVs) comprise a large genus of positive-sense, single-stranded RNA viruses whose members cause a number of important and widespread human diseases, including poliomyelitis, myocarditis, acute flaccid myelitis and the common cold. How EVs co-opt cellular functions to promote replication and spread is incompletely understood. Here, using genome-scale CRISPR screens, we identify the actin histidine methyltransferase SET domain containing 3 (SETD3) as critically important for viral infection by a broad panel of EVs, including rhinoviruses and non-polio EVs increasingly linked to severe neurological disease such as acute flaccid myelitis (EV-D68) and viral encephalitis (EV-A71). We show that cytosolic SETD3, independent of its methylation activity, is required for the RNA replication step in the viral life cycle. Using quantitative affinity purification-mass spectrometry, we show that SETD3 specifically interacts with the viral 2A protease of multiple enteroviral species, and we map the residues in 2A that mediate this interaction. 2A mutants that retain protease activity but are unable to interact with SETD3 are severely compromised in RNA replication. These data suggest a role of the viral 2A protein in RNA replication beyond facilitating proteolytic cleavage. Finally, we show that SETD3 is essential for in vivo replication and pathogenesis in multiple mouse models for EV infection, including CV-A10, EV-A71 and EV-D68. Our results reveal a crucial role of a host protein in viral pathogenesis, and suggest targeting SETD3 as a potential mechanism for controlling viral infections.

Identifiants

DOI: 10.1038/s41564-019-0551-1 PMID: 31527793 PMC: PMC6879830
pubmed: 31527793
doi: 10.1038/s41564-019-0551-1
pii: 10.1038/s41564-019-0551-1
pmc: PMC6879830
mid: NIHMS1535897
doi:

Substances chimiques

Viral Proteins 0
virus protein 2A 0
Histone Methyltransferases EC 2.1.1.-
Methyltransferases EC 2.1.1.-
Setd3 protein, mouse EC 2.1.1.-

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

2523-2537

Subventions

Organisme : NIAID NIH HHS
ID : DP2 AI104557
Pays : United States
Organisme : NIAID NIH HHS
ID : K99 AI135031
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI021362
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM081879
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM079641
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI140186
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI021362
Pays : United States
Organisme : NIAID NIH HHS
ID : P50 AI150476
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI091575
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI141970
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI109662
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM082250
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI130123
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI040085
Pays : United States
Organisme : BLRD VA
ID : I01 BX000158
Pays : United States

Références

Kaufmann, S. H. E., Dorhoi, A., Hotchkiss, R. S. & Bartenschlager, R. Host-directed therapies for bacterial and viral infections. Nat. Rev. Drug Discov. 17, 35–56 (2018).
pubmed: 28935918
Bramley, T. J., Lerner, D. & Sames, M. Productivity losses related to the common cold. J. Occup. Environ. Med. 44, 822–829 (2002).
pubmed: 12227674
Castillo, J. R., Peters, S. P. & Busse, W. W. Asthma exacerbations: pathogenesis, prevention, and treatment. J. Allergy Clin. Immunol. Pract. 5, 918–927 (2017).
pubmed: 28689842 pmcid: 5950727
Palmenberg, A. C. et al. Sequencing and analyses of all known human rhinovirus genomes reveal structure and evolution. Science 324, 55–59 (2009).
pubmed: 19213880 pmcid: 3923423
Cassidy, H., Poelman, R., Knoester, M., Van Leer-Buter, C. C. & Niesters, H. G. M. Enterovirus D68—the new polio? Front. Microbiol. 9, 2677 (2018).
pubmed: 30483226 pmcid: 6243117
Bochkov, Y. A. et al. Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication. Proc. Natl Acad. Sci. USA 112, 5485–5490 (2015).
pubmed: 25848009
Shalem, O. et al. Genome-scale CRISPR–Cas9 knockout screening in human cells. Science 343, 84–87 (2014).
pubmed: 24336571
Li, W. et al. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol. 15, 554 (2014).
pubmed: 25476604 pmcid: 4290824
Liu, Y. et al. Sialic acid-dependent cell entry of human enterovirus D68. Nat. Commun. 6, 8865 (2015).
pubmed: 26563423 pmcid: 4660200
Hunt, S. L., Hsuan, J. J., Totty, N. & Jackson, R. J. unr, a cellular cytoplasmic RNA-binding protein with five cold-shock domains, is required for internal initiation of translation of human rhinovirus RNA. Genes Dev. 13, 437–448 (1999).
pubmed: 10049359 pmcid: 316477
Staring, J. et al. PLA2G16 represents a switch between entry and clearance of Picornaviridae. Nature 541, 412–416 (2017).
pubmed: 28077878
Wilkinson, A. W. et al. SETD3 is an actin histidine methyltransferase that prevents primary dystocia. Nature 565, 372–376 (2019).
pubmed: 30626964
Kwiatkowski, S. et al. SETD3 protein is the actin-specific histidine N-methyltransferase. eLife 7, e37921 (2018).
pubmed: 30526847 pmcid: 6289574
Messacar, K. et al. Enterovirus D68 and acute flaccid myelitis-evaluating the evidence for causality. Lancet Infect. Dis. 18, e239–e247 (2018).
pubmed: 29482893 pmcid: 6778404
Chen, K. et al. Methyltransferase SETD2-mediated methylation of STAT1 is critical for interferon antiviral activity. Cell 170, 492–506 (2017).
pubmed: 28753426
Wang, C. et al. The methyltransferase NSD3 promotes antiviral innate immunity via direct lysine methylation of IRF3. J. Exp. Med. 214, 3597–3610 (2017).
pubmed: 29101251 pmcid: 5716042
Lamphear, B. J. et al. Mapping the cleavage site in protein synthesis initiation factor eIF-4γ of the 2A proteases from human coxsackievirus and rhinovirus. J. Biol. Chem. 268, 19200–19203 (1993).
pubmed: 8396129
Verschueren, E. et al. Scoring large-scale affinity purification mass spectrometry datasets with MiST. Curr. Protoc. Bioinformatics 49, 11–16 (2015).
Watters, K. & Palmenberg, A. C. Differential processing of nuclear pore complex proteins by rhinovirus 2A proteases from different species and serotypes. J. Virol. 85, 10874–10883 (2011).
pubmed: 21835805 pmcid: 3187490
Ventoso, I., MacMillan, S. E., Hershey, J. W. & Carrasco, L. Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F complex. FEBS Lett. 435, 79–83 (1998).
pubmed: 9755863
Greninger, A. L., Knudsen, G. M., Betegon, M., Burlingame, A. L. & Derisi, J. L. The 3A protein from multiple picornaviruses utilizes the golgi adaptor protein ACBD3 to recruit PI4KIIIβ. J. Virol. 86, 3605–3616 (2012).
pubmed: 22258260 pmcid: 3302542
Wessels, E. et al. A viral protein that blocks Arf1-mediated COP-I assembly by inhibiting the guanine nucleotide exchange factor GBF1. Dev. Cell 11, 191–201 (2006).
pubmed: 16890159
Torres, J. Z., Miller, J. J. & Jackson, P. K. High-throughput generation of tagged stable cell lines for proteomic analysis. Proteomics 9, 2888–2891 (2009).
pubmed: 19405035 pmcid: 4785821
Petersen, J. F. et al. The structure of the 2A proteinase from a common cold virus: a proteinase responsible for the shut-off of host-cell protein synthesis. EMBO J. 18, 5463–5475 (1999).
pubmed: 10523291 pmcid: 1171615
Yu, S. F. & Lloyd, R. E. Characterization of the roles of conserved cysteine and histidine residues in poliovirus 2A protease. Virology 186, 725–735 (1992).
pubmed: 1310193
Dickinson, M. E. et al. High-throughput discovery of novel developmental phenotypes. Nature 537, 508–514 (2016).
pubmed: 27626380 pmcid: 5295821
Huang, P. N. & Shih, S. R. Update on enterovirus 71 infection. Curr. Opin. Virol. 5, 98–104 (2014).
pubmed: 24727707
Li, S. et al. A neonatal mouse model of coxsackievirus A10 infection for anti-viral evaluation. Antivir. Res. 144, 247–255 (2017).
pubmed: 28625478
Huang, S. W., Wang, Y. F., Yu, C. K., Su, I. J. & Wang, J. R. Mutations in VP2 and VP1 capsid proteins increase infectivity and mouse lethality of enterovirus 71 by virus binding and RNA accumulation enhancement. Virology 422, 132–143 (2012).
pubmed: 22078110
Hambidge, S. J. & Sarnow, P. Translational enhancement of the poliovirus 5′ noncoding region mediated by virus-encoded polypeptide 2A. Proc. Natl Acad. Sci. USA 89, 10272–10276 (1992).
pubmed: 1332040
Li, X., Lu, H. H., Mueller, S. & Wimmer, E. The C-terminal residues of poliovirus proteinase 2A
pubmed: 11161279
Lloyd, R. E., Grubman, M. J. & Ehrenfeld, E. Relationship of p220 cleavage during picornavirus infection to 2A proteinase sequencing. J. Virol. 62, 4216–4223 (1988).
pubmed: 2845133 pmcid: 253854
Ryan, M. D. & Flint, M. Virus-encoded proteinases of the picornavirus super-group. J. Gen. Virol. 78, 699–723 (1997).
pubmed: 9129643
Hoshii, T. et al. A non-catalytic function of SETD1A regulates cyclin K and the DNA damage response. Cell 172, 1007–1021 (2018).
pubmed: 29474905 pmcid: 6052445
Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 16, 101–114 (2017).
pubmed: 27885283
Lanke, K. H. et al. GBF1, a guanine nucleotide exchange factor for Arf, is crucial for coxsackievirus B3 RNA replication. J. Virol. 83, 11940–11949 (2009).
pubmed: 19740986 pmcid: 2772713
Bochkov, Y. A. et al. Molecular modeling, organ culture and reverse genetics for a newly identified human rhinovirus C. Nat. Med. 17, 627–632 (2011).
pubmed: 21483405 pmcid: 3089712
Sanjana, N. E., Shalem, O. & Zhang, F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods 11, 783–784 (2014).
pubmed: 25075903 pmcid: 4486245
Marceau, C. D. et al. Genetic dissection of flaviviridae host factors through genome-scale CRISPR screens. Nature 535, 159–163 (2016).
pubmed: 27383987 pmcid: 4964798
Verstrepen, W. A., Kuhn, S., Kockx, M. M., Van De Vyvere, M. E. & Mertens, A. H. Rapid detection of enterovirus RNA in cerebrospinal fluid specimens with a novel single-tube real-time reverse transcription-PCR assay. J. Clin. Microbiol. 39, 4093–4096 (2001).
pubmed: 11682535 pmcid: 88492
Bragstad, K. et al. High frequency of enterovirus D68 in children hospitalised with respiratory illness in Norway, autumn 2014. Influenza Other Resp. Viruses 9, 59–63 (2015).
McKnight, K. L. & Lemon, S. M. Capsid coding sequence is required for efficient replication of human rhinovirus 14 RNA. J. Virol. 70, 1941–1952 (1996).
pubmed: 8627720 pmcid: 190023
Ding, S. et al. Comparative proteomics reveals strain-specific β-TrCP degradation via rotavirus NSP1 hijacking a host Cullin-3-Rbx1 complex. PLoS Pathog. 12, e1005929 (2016).
pubmed: 27706223 pmcid: 5051689
Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008).
pubmed: 19029910
Kron, S. J., Drubin, D. G., Botstein, D. & Spudich, J. A. Yeast actin filaments display ATP-dependent sliding movement over surfaces coated with rabbit muscle myosin. Proc. Natl Acad. Sci. USA 89, 4466–4470 (1992).
pubmed: 1533933
Schafer, D. A., Jennings, P. B. & Cooper, J. A. Rapid and efficient purification of actin from nonmuscle sources. Cell Motil. Cytoskeleton 39, 166–171 (1998).
pubmed: 9484958 pmcid: 2362386
Ramage, H. R. et al. A combined proteomics/genomics approach links hepatitis C virus infection with nonsense-mediated mRNA decay. Mol. Cell 57, 329–340 (2015).
pubmed: 25616068 pmcid: 4305532
Clauser, K. R., Baker, P. & Burlingame, A. L. Role of accurate mass measurement (±10 ppm) in protein identification strategies employing MS or MS/MS and database searching. Anal. Chem. 71, 2871–2882 (1999).
pubmed: 10424174
Duke, G. M., Hoffman, M. A. & Palmenberg, A. C. Sequence and structural elements that contribute to efficient encephalomyocarditis virus RNA translation. J. Virol. 66, 1602–1609 (1992).
pubmed: 1310768 pmcid: 240893
Jager, S. et al. Global landscape of HIV–human protein complexes. Nature 481, 365–370 (2011).
pubmed: 22190034 pmcid: 3310911
Jager, S. et al. Purification and characterization of HIV–human protein complexes. Methods 53, 13–19 (2011).
pubmed: 20708689
MacLean, B. et al. Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatica 26, 966–968 (2010).
Choi, M. et al. MSstats: an R package for statistical analysis of quantitative mass spectrometry-based proteomic experiments. Bioinformatica 30, 2524–2526 (2014).
Watters, K. et al. Differential disruption of nucleocytoplasmic trafficking pathways by rhinovirus 2A proteases. J. Virol. 91, e02472–16 (2017).
pubmed: 28179529 pmcid: 5375692
National Research Council. Guide for the Care and Use of Laboratory Animals 8th edn (National Academies Press, 2010).
U.S. Department of Health and Human Services National Institutes of Health. Public Health Service Policy on Humane Care and Use of Laboratory Animals (Office of Laboratory Animal Welfare, 2015).
Mao, Q. et al. A neonatal mouse model of coxsackievirus A16 for vaccine evaluation. J. Virol. 86, 11967–11976 (2012).
pubmed: 22951825 pmcid: 3486452
Bradley, A. et al. The mammalian gene function resource: the International Knockout Mouse Consortium. Mamm. Genome 23, 580–586 (2012).
pubmed: 22968824 pmcid: 3463800
Li, J. & Daly, T. M. Adeno-associated virus-mediated gene transfer to the neonatal brain. Methods 28, 203–207 (2002).
pubmed: 12413418
Hixon, A. M. et al. A mouse model of paralytic myelitis caused by enterovirus D68. PLoS Pathog. 13, e1006199 (2017).
pubmed: 28231269 pmcid: 5322875

Auteurs

Jonathan Diep (J)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.

Yaw Shin Ooi (YS)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
ORCID: 0000-0001-9014-1365

Alex W Wilkinson (AW)

Department of Biology, Stanford University, Stanford, CA, USA.

Christine E Peters (CE)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.

Eileen Foy (E)

Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.

Jeffrey R Johnson (JR)

Department of Cellular Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA.
The J. David Gladstone Institutes, San Francisco, CA, USA.

James Zengel (J)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.

Siyuan Ding (S)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA, USA.

Kuo-Feng Weng (KF)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.

Orly Laufman (O)

Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.

Gwendolyn Jang (G)

Department of Cellular Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA.
The J. David Gladstone Institutes, San Francisco, CA, USA.

Jiewei Xu (J)

Department of Cellular Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA.
The J. David Gladstone Institutes, San Francisco, CA, USA.

Tracy Young (T)

Department of Cellular Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.

Erik Verschueren (E)

Department of Cellular Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.

Kristi J Kobluk (KJ)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.

Joshua E Elias (JE)

Chan Zuckerberg Biohub, Mass Spectrometry Platform, Stanford, CA, USA.

Peter Sarnow (P)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.

Harry B Greenberg (HB)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA, USA.

Ruth Hüttenhain (R)

Department of Cellular Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA.
The J. David Gladstone Institutes, San Francisco, CA, USA.

Claude M Nagamine (CM)

Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Raul Andino (R)

Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. raul.andino@ucsf.edu.
ORCID: 0000-0001-5503-9349

Nevan J Krogan (NJ)

Department of Cellular Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. nevan.krogan@gladstone.ucsf.edu.
Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA. nevan.krogan@gladstone.ucsf.edu.
The J. David Gladstone Institutes, San Francisco, CA, USA. nevan.krogan@gladstone.ucsf.edu.
ORCID: 0000-0003-4902-337X

Or Gozani (O)

Department of Biology, Stanford University, Stanford, CA, USA. ogozani@stanford.edu.
ORCID: 0000-0002-1365-4463

Jan E Carette (JE)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. carette@stanford.edu.
ORCID: 0000-0002-5187-8070

Articles similaires

Evaluating the efficacy of telesurgery with dual console SSI Mantra Surgical Robotic System: experiment on animal model and clinical trials.

Sudhir Prem Srivastava, Vishwajyoti Pascual Srivastava, Avinesh Singh et al.
1.00
Robotic Surgical Procedures Animals Humans Telemedicine Models, Animal

Odour generalisation and detection dog training.

Lyn Caldicott, Thomas W Pike, Helen E Zulch et al.
1.00
Animals Odorants Dogs Generalization, Psychological Smell

FBXO22 inhibits colitis and colorectal carcinogenesis by regulating the degradation of the S2448-phosphorylated form of mTOR.

Minle Li, Xuan Chen, Pengfei Qu et al.
1.00
Animals TOR Serine-Threonine Kinases Colorectal Neoplasms Colitis Mice

Use of organic material provided by an automatic enrichment device by weaner pigs and its influence on tail lesions.

Philipp Heseker, Jeanette Probst, Stefanie Ammer et al.
1.00
Animals Tail Swine Behavior, Animal Animal Husbandry

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Extinction de l'expression des gènes › Systèmes CRISPR-Cas › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Infections du système nerveux central › Maladies virales du système nerveux central › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Maladies du système nerveux › Encéphalite › Encéphalite infectieuse › Encéphalite virale › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Picornaviridae › Enterovirus › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Infection › Maladies virales › Infections à virus à ARN › Infections à Picornaviridae › Infections à entérovirus › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › Protein Methyltransferases › Histone méthyltransférases › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Maladies du système nerveux › Myélite › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Maladies du système nerveux › Maladies neuromusculaires › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Métabolisme › Protéolyse › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines virales › Enterovirus pathogenesis requires the host...
questionsmedicales.fr › Phénomènes microbiologiques › Phénomènes physiologiques viraux › Réplication virale › Enterovirus pathogenesis requires the host...