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Novel residues in avian influenza virus PB2 protein affect virulence in mammalian hosts.

ABSTRACT: Highly pathogenic avian H5N1 influenza viruses have sporadically transmitted to humans causing high mortality. The mechanistic basis for adaptation is still poorly understood, although several residues in viral protein PB2 are known to be important for this event. Here, we demonstrate that three residues, 147T, 339T and 588T, in PB2 play critical roles in the virulence of avian H5N1 influenza viruses in a mammalian host in vitro and in vivo and, together, result in a phenotype comparable to that conferred by the previously known PB2-627K mutation with respect to virus polymerase activity. A virus with the three residues and 627K in PB2, as has been isolated from a lethal human case, is more pathogenic than viruses with only the three residues or 627K in PB2. Importantly, H5N1 viruses bearing the former three PB2 residues have circulated widely in recent years in avian species in nature.

SUBMITTER: Fan S

PROVIDER: S-EPMC5841464 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Novel residues in avian influenza virus PB2 protein affect virulence in mammalian hosts.

Fan Shufang S Hatta Masato M Kim Jin Hyun JH Halfmann Peter P Imai Masaki M Macken Catherine A CA Le Mai Quynh MQ Nguyen Tung T Neumann Gabriele G Kawaoka Yoshihiro Y

Nature communications 20141007

Highly pathogenic avian H5N1 influenza viruses have sporadically transmitted to humans causing high mortality. The mechanistic basis for adaptation is still poorly understood, although several residues in viral protein PB2 are known to be important for this event. Here, we demonstrate that three residues, 147T, 339T and 588T, in PB2 play critical roles in the virulence of avian H5N1 influenza viruses in a mammalian host in vitro and in vivo and, together, result in a phenotype comparable to that ...[more]

PMID: 25289523

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Project description:Since the first human infection reported in 2013, H7N9 avian influenza virus (AIV) has been regarded as a serious threat to human health. In this study, we sought to identify the virulence determinant of the H7N9 virus in mammalian hosts. By comparing the virulence of the SH/4664 H7N9 virus, a non-virulent H9N2 virus, and various H7N9-H9N2 hybrid viruses in infected mice, we first pinpointed PB2 as the primary viral factor accounting for the difference between H7N9 and H9N2 in mammalian virulence. We further analyzed the in vivo effects of individually mutating H7N9 PB2 residues different from the closely related H9N2 virus and consequently found residue 473, alongside the well-known residue 627, to be critical for the virulence of the H7N9 virus in mice and the activity of its reconstituted viral polymerase in mammalian cells. The importance of PB2-473 was further strengthened by studying reverse H7N9 substitutions in the H9N2 background. Finally, we surprisingly found that species-specific usage of ANP32A, a family member of host factors connecting with the PB2-627 polymorphism, mediates the contribution of PB2 473 residue to the mammalian adaption of AIV polymerase, as the attenuating effect of PB2 M473T on the viral polymerase activity and viral growth of the H7N9 virus could be efficiently complemented by co-expression of chicken ANP32A but not mouse ANP32A and ANP32B. Together, our studies uncovered the PB2 473 residue as a novel viral host range determinant of AIVs via species-specific co-opting of the ANP32 host factor to support viral polymerase activity.IMPORTANCEThe H7N9 avian influenza virus has been considered to have the potential to cause the next pandemic since the first case of human infection reported in 2013. In this study, we identified PB2 residue 473 as a new determinant of mouse virulence and mammalian adaptation of the viral polymerase of the H7N9 virus and its non-pathogenic H9N2 counterparts. We further demonstrated that the variation in PB2-473 is functionally linked to differential co-opting of the host ANP32A protein in supporting viral polymerase activity, which is analogous to the well-known PB2-627 polymorphism, albeit the two PB2 positions are spatially distant. By providing new mechanistic insight into the PB2-mediated host range determination of influenza A viruses, our study implicated the potential existence of multiple PB2-ANP32 interfaces that could be targets for developing new antivirals against the H7N9 virus as well as other mammalian-adapted influenza viruses.

Project description:UnlabelledMutations in the polymerase genes are known to play a major role in avian influenza virus adaptation to mammalian hosts. Despite having avian origin PA and PB2, the 2009 pandemic H1N1 virus (pH1N1) can replicate well in mammalian respiratory tracts, suggesting that these proteins have acquired mutations for efficient growth in humans. We have previously shown that PA from the pH1N1 virus A/California/04/09 (Cal) strongly enhances activity of an otherwise avian polymerase complex derived from A/chicken/Nanchang/3-120/01 (Nan) in mammalian cells. However, this enhancement was observed at 37°C but not at the lower temperature of 34°C. An additional introduction of Cal PB2 enhanced activity at 34°C, suggesting the presence of unidentified residues in Cal PB2 that are required for efficient growth at low temperature. Here, we sought to determine the key PB2 residues which confer enhanced polymerase activity and virus growth in human cells at low temperature. Using a reporter gene assay, we identified novel mutations, PB2 V661A and V683T/A684S, which are involved in enhanced Cal polymerase activity at low temperature. The PB2 T271A mutation, which we previously reported, also contributed to enhanced activity. The growth of recombinant Cal containing PB2 with Nan residues 271T/661V/683V/684A was strongly reduced in human cells compared to wild-type virus at low temperature. Among the four residues, 271A and 684S are conserved in human and pH1N1 viruses but not in avian viruses, suggesting an important role in mammalian adaptation of pH1N1 virus.ImportanceThe PB2 protein plays a key role in the host adaptation, cold sensitivity, and pathogenesis of influenza A virus. Despite containing an avian origin PB2 lacking the mammalian adaptive mutations 627K or 701N, pH1N1 influenza virus strains can replicate efficiently in the low temperature upper respiratory tract of mammals, suggesting the presence of unknown mutations in the pH1N1 PB2 protein responsible for its low temperature adaptation. Here, in addition to PB2 271A, which has been shown to increase polymerase activity, we identified novel PB2 residues 661A and 683T/684S in pH1N1 which confer enhanced polymerase activity and virus growth in mammalian cells especially at low temperature. Our findings suggest that the presence of these PB2 residues contributes to efficient replication of the pH1N1 virus in the upper respiratory tract, which resulted in efficient human-to-human transmission of this virus.

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Novel residues in avian influenza virus PB2 protein affect virulence in mammalian hosts.

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Novel residues in avian influenza virus PB2 protein affect virulence in mammalian hosts.

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