Host- and Strain-Specific Regulation of Influenza Virus Polymerase Activity by Interacting Cellular Proteins

ABSTRACT Highly pathogenic avian influenza A (HPAI) viruses of the H5N1 subtype have recently emerged from avian zoonotic reservoirs to cause fatal human disease. Adaptation of HPAI virus RNA-dependent RNA polymerase (PB1, PB2, and PA proteins) and nucleoprotein (NP) to interactions with mammalian h...

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Autores principales:	Eric Bortz, Liset Westera, Jad Maamary, John Steel, Randy A. Albrecht, Balaji Manicassamy, Geoffrey Chase, Luis Martínez-Sobrido, Martin Schwemmle, Adolfo García-Sastre
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2011
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ca34bbf134f14f6dabe7f0d60ab0c2a6
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spelling	oai:doaj.org-article:ca34bbf134f14f6dabe7f0d60ab0c2a62021-11-15T15:38:45ZHost- and Strain-Specific Regulation of Influenza Virus Polymerase Activity by Interacting Cellular Proteins10.1128/mBio.00151-112150-7511https://doaj.org/article/ca34bbf134f14f6dabe7f0d60ab0c2a62011-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00151-11https://doaj.org/toc/2150-7511ABSTRACT Highly pathogenic avian influenza A (HPAI) viruses of the H5N1 subtype have recently emerged from avian zoonotic reservoirs to cause fatal human disease. Adaptation of HPAI virus RNA-dependent RNA polymerase (PB1, PB2, and PA proteins) and nucleoprotein (NP) to interactions with mammalian host proteins is thought to contribute to the efficiency of viral RNA synthesis and to disease severity. While proteomics experiments have identified a number of human proteins that associate with H1N1 polymerases and/or viral ribonucleoprotein (vRNP), how these host interactions might regulate influenza virus polymerase functions and host adaptation has been largely unexplored. We took a functional genomics (RNA interference [RNAi]) approach to assess the roles of a network of human proteins interacting with influenza virus polymerase proteins in viral polymerase activity from prototype H1N1 and H5N1 viruses. A majority (18 of 31) of the cellular proteins tested, including RNA-binding (DDX17, DDX5, NPM1, and hnRNPM), stress (PARP1, DDB1, and Ku70/86), and intracellular transport proteins, were required for efficient activity of both H1N1 and H5N1 polymerases. NXP2 and NF90 antagonized both polymerases, and six more RNA-associated proteins exhibited strain-specific phenotypes. Remarkably, 12 proteins differentially regulated H5N1 polymerase according to PB2 genotype at mammalian-adaptive residue 627. Among these, DEAD box RNA helicase DDX17/p72 facilitated efficient human-adapted (627K) H5N1 virus mRNA and viral RNA (vRNA) synthesis in human cells. Likewise, the chicken DDX17 homologue was required for efficient avian (627E) H5N1 infection in chicken DF-1 fibroblasts, suggesting that this conserved virus-host interaction contributes to PB2-dependent host species specificity of influenza virus and ultimately to the outcome of human HPAI infections. IMPORTANCE Highly pathogenic avian influenza A (HPAI) viruses have recently emerged from wild and domestic birds to cause fatal human disease. In human patients, it is thought that adaptation of the viral polymerase, a complex of viral proteins responsible for viral gene expression and RNA genome replication, to interactions with mammalian rather than avian host proteins contributes to disease severity. In this study, we used computational analysis and RNA interference (RNAi) experiments to identify a biological network of human proteins that regulates an H5N1 HPAI virus polymerase, in comparison to a mammalian H1N1 virus. Of 31 proteins tested, 18 (58%) were required for polymerase function in both HPAI and H1N1 viruses. Remarkably, we also found proteins such as DDX17 that governed the HPAI virus polymerase’s adaptation to human cells. These virus-host interactions may thus control pathogenicity of HPAI virus in humans and are promising therapeutic targets for antiviral drugs in severe influenza infections.Eric BortzLiset WesteraJad MaamaryJohn SteelRandy A. AlbrechtBalaji ManicassamyGeoffrey ChaseLuis Martínez-SobridoMartin SchwemmleAdolfo García-SastreAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 2, Iss 4 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Eric Bortz Liset Westera Jad Maamary John Steel Randy A. Albrecht Balaji Manicassamy Geoffrey Chase Luis Martínez-Sobrido Martin Schwemmle Adolfo García-Sastre Host- and Strain-Specific Regulation of Influenza Virus Polymerase Activity by Interacting Cellular Proteins
description	ABSTRACT Highly pathogenic avian influenza A (HPAI) viruses of the H5N1 subtype have recently emerged from avian zoonotic reservoirs to cause fatal human disease. Adaptation of HPAI virus RNA-dependent RNA polymerase (PB1, PB2, and PA proteins) and nucleoprotein (NP) to interactions with mammalian host proteins is thought to contribute to the efficiency of viral RNA synthesis and to disease severity. While proteomics experiments have identified a number of human proteins that associate with H1N1 polymerases and/or viral ribonucleoprotein (vRNP), how these host interactions might regulate influenza virus polymerase functions and host adaptation has been largely unexplored. We took a functional genomics (RNA interference [RNAi]) approach to assess the roles of a network of human proteins interacting with influenza virus polymerase proteins in viral polymerase activity from prototype H1N1 and H5N1 viruses. A majority (18 of 31) of the cellular proteins tested, including RNA-binding (DDX17, DDX5, NPM1, and hnRNPM), stress (PARP1, DDB1, and Ku70/86), and intracellular transport proteins, were required for efficient activity of both H1N1 and H5N1 polymerases. NXP2 and NF90 antagonized both polymerases, and six more RNA-associated proteins exhibited strain-specific phenotypes. Remarkably, 12 proteins differentially regulated H5N1 polymerase according to PB2 genotype at mammalian-adaptive residue 627. Among these, DEAD box RNA helicase DDX17/p72 facilitated efficient human-adapted (627K) H5N1 virus mRNA and viral RNA (vRNA) synthesis in human cells. Likewise, the chicken DDX17 homologue was required for efficient avian (627E) H5N1 infection in chicken DF-1 fibroblasts, suggesting that this conserved virus-host interaction contributes to PB2-dependent host species specificity of influenza virus and ultimately to the outcome of human HPAI infections. IMPORTANCE Highly pathogenic avian influenza A (HPAI) viruses have recently emerged from wild and domestic birds to cause fatal human disease. In human patients, it is thought that adaptation of the viral polymerase, a complex of viral proteins responsible for viral gene expression and RNA genome replication, to interactions with mammalian rather than avian host proteins contributes to disease severity. In this study, we used computational analysis and RNA interference (RNAi) experiments to identify a biological network of human proteins that regulates an H5N1 HPAI virus polymerase, in comparison to a mammalian H1N1 virus. Of 31 proteins tested, 18 (58%) were required for polymerase function in both HPAI and H1N1 viruses. Remarkably, we also found proteins such as DDX17 that governed the HPAI virus polymerase’s adaptation to human cells. These virus-host interactions may thus control pathogenicity of HPAI virus in humans and are promising therapeutic targets for antiviral drugs in severe influenza infections.
format	article
author	Eric Bortz Liset Westera Jad Maamary John Steel Randy A. Albrecht Balaji Manicassamy Geoffrey Chase Luis Martínez-Sobrido Martin Schwemmle Adolfo García-Sastre
author_facet	Eric Bortz Liset Westera Jad Maamary John Steel Randy A. Albrecht Balaji Manicassamy Geoffrey Chase Luis Martínez-Sobrido Martin Schwemmle Adolfo García-Sastre
author_sort	Eric Bortz
title	Host- and Strain-Specific Regulation of Influenza Virus Polymerase Activity by Interacting Cellular Proteins
title_short	Host- and Strain-Specific Regulation of Influenza Virus Polymerase Activity by Interacting Cellular Proteins
title_full	Host- and Strain-Specific Regulation of Influenza Virus Polymerase Activity by Interacting Cellular Proteins
title_fullStr	Host- and Strain-Specific Regulation of Influenza Virus Polymerase Activity by Interacting Cellular Proteins
title_full_unstemmed	Host- and Strain-Specific Regulation of Influenza Virus Polymerase Activity by Interacting Cellular Proteins
title_sort	host- and strain-specific regulation of influenza virus polymerase activity by interacting cellular proteins
publisher	American Society for Microbiology
publishDate	2011
url	https://doaj.org/article/ca34bbf134f14f6dabe7f0d60ab0c2a6
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Host- and Strain-Specific Regulation of Influenza Virus Polymerase Activity by Interacting Cellular Proteins

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