Species difference in ANP32A underlies influenza A virus polymerase host restriction

Long, Jason S.; Giotis, Efstathios S.; Moncorgé, Olivier; Frise, Rebecca; Mistry, Bhakti; James, Joe; Morisson, Mireille; Iqbal, Munir; Vignal, Alain; Skinner, Michael A.; Barclay, William

doi:10.1038/nature16474

Cited by 255 publications

(396 citation statements)

References 44 publications

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“…Previous studies have extensively documented species-specific host factors in restricting HIV replication (Mariani et al, 2003; Stremlau et al, 2004). Recent work has also extended this theme into the cross-species restriction of flaviviruses, herpesviruses (Aguirre et al, 2012; Lou et al, 2016; Patel et al, 2012) and influenza virus (Long et al, 2016; Meyerson et al, 2017). These studies provide critical mechanistic insight into the barrier of cross-species transmission of viruses.…”

Section: Discussionmentioning

confidence: 99%

Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication

Zhang

Zhao

et al. 2018

Cell Host & Microbe

157

143

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SUMMARY Herpes simplex virus-1 (HSV-1) establishes infections in humans and mice but some non-human primates exhibit resistance via unknown mechanisms. Innate immune recognition pathways are highly conserved but are pivotal in determining susceptibility to DNA virus infections. We report that variation of a single amino acid residue in the innate immune sensor cGAS determines species-specific inactivation by HSV-1. The HSV-1 UL37 tegument protein deamidates human and mouse cGAS. Deamidation impairs the ability of cGAS to catalyze cGAMP synthesis, which activates innate immunity. HSV-1 with deamidase-deficient UL37 promotes robust antiviral responses and is attenuated in mice, in a cGAS- and STING-dependent manner. Mutational analyses identified a single asparagine in human and mouse cGAS that is not conserved in many non-human primates. This residue underpins UL37-mediated cGAS deamidation and species permissiveness of HSV-1. Thus, HSV-1 mediates cGAS deamidation for immune evasion and exploits species sequence variation to disarm host defenses.

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Section: Discussionmentioning

confidence: 99%

Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication

Zhang

Zhao

et al. 2018

Cell Host & Microbe

157

143

View full text Add to dashboard Cite

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“…However, more research is necessary to understand the mechanisms by which these substitutions increase overall polymerase activity. In avian cells, a recently identified potent polymerase-enhancing factor might render the need for further enhancing mutations obsolete (40). During the first half of 2015, there were already more than 300 human cases of infection with H5N1 and H7N9 viruses (http: //www.who.int), demonstrating the topicality of both subtypes.…”

Section: Discussionmentioning

confidence: 99%

Multiple Natural Substitutions in Avian Influenza A Virus PB2 Facilitate Efficient Replication in Human Cells

Mänz

Graaf

Mögling

et al. 2016

J Virol

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A strong restriction of the avian influenza A virus polymerase in mammalian cells generally limits viral host-range switching. Although substitutions like E627K in the PB2 polymerase subunit can facilitate polymerase activity to allow replication in mammals, many human H5N1 and H7N9 viruses lack this adaptive substitution. Here, several previously unknown, naturally occurring, adaptive substitutions in PB2 were identified by bioinformatics, and their enhancing activity was verified using in vitro assays. Adaptive substitutions enhanced polymerase activity and virus replication in mammalian cells for avian H5N1 and H7N9 viruses but not for a partially human-adapted H5N1 virus. Adaptive substitutions toward basic amino acids were frequent and were mostly clustered in a putative RNA exit channel in a polymerase crystal structure. Phylogenetic analysis demonstrated divergent dependency of influenza viruses on adaptive substitutions. The novel adaptive substitutions found in this study increase basic understanding of influenza virus host adaptation and will help in surveillance efforts. IMPORTANCEInfluenza viruses from birds jump the species barrier into humans relatively frequently. Such influenza virus zoonoses may pose public health risks if the virus adapts to humans and becomes a pandemic threat. Relatively few amino acid substitutions-most notably in the receptor binding site of hemagglutinin and at positions 591 and 627 in the polymerase protein PB2-have been identified in pandemic influenza virus strains as determinants of host adaptation, to facilitate efficient virus replication and transmission in humans. Here, we show that substantial numbers of amino acid substitutions are functionally compensating for the lack of the above-mentioned mutations in PB2 and could facilitate influenza virus emergence in humans.

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“…Acidic nuclear phosphoprotein 32 family member A (ANP32A, pp32) associates with the influenza A virus polymerase and stimulates vRNA synthesis from a cRNA template in vitro (Bradel-Tretheway et al, 2011; Sugiyama et al, 2015). More recently, ANP32A has been shown to affect the host range of influenza virus as a species-specific co-factor of the viral polymerase (Long et al, 2016). The restriction of avian-origin polymerases in mammalian cells is overcome by expressing avian ANP32A in these cells.…”

Section: Introductionmentioning

confidence: 99%

Differential Splicing of ANP32A in Birds Alters Its Ability to Stimulate RNA Synthesis by Restricted Influenza Polymerase

2018

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SUMMARY Adaptation of viruses to their hosts can result in specialization and a restricted host range. Species specific polymorphisms in the influenza virus polymerase restrict its host range during transmission from birds to mammals. ANP32A was recently identified as a cellular co-factor affecting polymerase adaption and activity. Avian influenza polymerases require ANP32A containing an insertion resulting from an exon duplication uniquely encoded in birds. Here we find that natural splice variants surrounding this exon create avian ANP32A proteins with distinct effects on polymerase activity. We demonstrate species-independent direct interactions between all ANP32A variants and the PB2 polymerase subunit. This interaction is enhanced in the presence of viral genomic RNA. In contrast, only avian ANP32A restored ribonucleoprotein complex assembly for a restricted polymerase by enhancing RNA synthesis. Our data suggest that ANP32A splicing variation among birds differentially affects viral replication, polymerase adaption, and the potential of avian hosts to be reservoirs.

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Species difference in ANP32A underlies influenza A virus polymerase host restriction

Cited by 255 publications

References 44 publications

Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication

Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication

Multiple Natural Substitutions in Avian Influenza A Virus PB2 Facilitate Efficient Replication in Human Cells

Differential Splicing of ANP32A in Birds Alters Its Ability to Stimulate RNA Synthesis by Restricted Influenza Polymerase

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