Identification of Amino Acid Changes That May Have Been Critical for the Genesis of A(H7N9) Influenza Viruses

Macken, Catherine A.; Kawaoka, Yoshihiro

doi:10.1128/jvi.00107-14

Cited by 39 publications

(38 citation statements)

References 88 publications

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“…In total, recent H7N9 NPs harbor three common changes in amino acid positions from VN/04 (Fig. 4A) (3,38). Analysis of the predicted crystal structure of SH/1-NP revealed that position 52 is surface exposed and is found in the center of the amino acid cluster determining Mx resistance (Mx patch) of BM/18 and descendant human strains, including PR/8 (22,38) (Fig.…”

Section: /2004 (Vn/04mentioning

confidence: 99%

The Nucleoprotein of Newly Emerged H7N9 Influenza A Virus Harbors a Unique Motif Conferring Resistance to Antiviral Human MxA

Riegger

Hai

Dornfeld

et al. 2015

J Virol

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Interferon-induced Mx proteins show strong antiviral activity against influenza A viruses (IAVs).We recently demonstrated that the viral nucleoprotein (NP) determines resistance of seasonal and pandemic human influenza viruses to Mx, while avian isolates retain Mx sensitivity. We identified a surface-exposed cluster of amino acids in NP of pandemic A/BM/1/1918 (H1N1), comprising isoleucine-100, proline-283, and tyrosine-313, that is essential for reduced Mx sensitivity in cell culture and in vivo. This cluster has been maintained in all descendant seasonal strains, including A/PR/8/34 (PR/8). Accordingly, two substitutions in the NP of PR/8 [PR/8(mut)] to the Mx-sensitive amino acids (P283L and Y313F) led to attenuation in Mx1-positive mice. Serial lung passages of PR/8(mut) in Mx1 mice resulted in a single exchange of tyrosine to asparagine at position 52 in NP (in close proximity to the amino acid cluster at positions 100, 283, and 313), which partially compensates loss of Mx resistance in PR/8(mut). Intriguingly, the NP of the newly emerged avian-origin H7N9 virus also contains an asparagine at position 52 and shows reduced Mx sensitivity. N52Y substitution in NP results in increased sensitivity of the H7N9 virus to human Mx, indicating that this residue is a determinant of Mx resistance in mammals. Our data strengthen the hypothesis that the human Mx protein represents a potent barrier against zoonotic transmission of avian influenza viruses. However, the H7N9 viruses overcome this restriction by harboring an NP that is less sensitive to Mx-mediated host defense. This might contribute to zoonotic transmission of H7N9 and to the severe to fatal outcome of H7N9 infections in humans. IMPORTANCEThe natural host of influenza A viruses (IAVs) are aquatic birds. Occasionally, these viruses cross the species barrier, as in early 2013 when an avian H7N9 virus infected humans in China. Since then, multiple transmissions of H7N9 viruses to humans have occurred, leaving experts puzzled about molecular causes for such efficient crossing of the species barrier compared to other avian influenza viruses. Mx proteins are known restriction factors preventing influenza virus replication. Unfortunately, some viruses (e.g., human IAV) have developed some resistance, which is associated with specific amino acids in their nucleoproteins, the target of Mx function. Here, we demonstrate that the novel H7N9 bird IAV already carries a nucleoprotein that overcomes the inhibition of viral replication by human MxA. This is the first example of an avian IAV that is naturally less sensitive to Mxmediated inhibition and might explain why H7N9 viruses transmitted efficiently to humans. In 2013 a new H7N9 variant of avian influenza A virus (IAV) was transmitted from birds to humans, causing more than 300 cases of severe disease with often fatal outcomes (1, 2). The unusual, relatively high number of human infections caused by this virus correlated with several adaptations to the mammalian host, including changes in the hemagglutinin ...

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Section: /2004 (Vn/04mentioning

confidence: 99%

The Nucleoprotein of Newly Emerged H7N9 Influenza A Virus Harbors a Unique Motif Conferring Resistance to Antiviral Human MxA

Riegger

Hai

Dornfeld

et al. 2015

J Virol

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“…Neumann et al recently identified a number of critical amino acid changes in the PA gene of ancestral H9N2 lineages, including the PA-K356R mutation, that contributed to the emergent avian H7N9 viruses that readily cause severe human infections (26). However, in the A/Anhui/1/2013 (H7N9) virus background, the reverse (avian-like) mutant PA-R356K appears to have little effect on viral polymerase activity and virulence in vitro and in vivo (28).…”

Section: Figmentioning

confidence: 99%

“…However, little is known about host adaptive mutations in the PA protein of avian H9N2 influenza viruses. Recently, comprehensive phylogenetic and ancestral inference analyses revealed a number of amino acid changes of avian H9N2 viruses, including K356R of PA, which may contribute to the evolutionary path of H7N9 viruses in humans (26). By analyzing the sequence and crystal structure of the PA subunit, Xu et al also hypothesized that PA-356R is a possible signature of avian H7N9 viruses with bird-to-human transmissibility (27).…”

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Prevailing PA Mutation K356R in Avian Influenza H9N2 Virus Increases Mammalian Replication and Pathogenicity

Zhang

Gao

et al. 2016

J Virol

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Adaptation of the viral polymerase complex comprising PB1, PB2, and PA is necessary for efficient influenza A virus replication in new host species. We found that PA mutation K356R (PA-K356R) has become predominant since 2014 in avian H9N2 viruses in China as with seasonal human H1N1 viruses. The same mutation is also found in most human isolates of emergent avian H7N9 and H10N8 viruses whose six internal gene segments are derived from the H9N2 virus. We further demonstrated the mammalian adaptive functionality of the PA-K356R mutation. Avian H9N2 virus with the PA-K356R mutation in human A549 cells showed increased nuclear accumulation of PA and increased viral polymerase activity that resulted in elevated levels of viral transcription and virus output. The same mutant virus in mice also enhanced virus replication and caused lethal infection. In addition, combined mutation of PA-K356R and PB2-E627K, a well-known mammalian adaptive marker, in the H9N2 virus showed further cooperative increases in virus production and severity of infection in vitro and in vivo. In summary, PA-K356R behaves as a novel mammalian tropism mutation, which, along with other mutations such as PB2-E627K, might render avian H9N2 viruses adapted for human infection. IMPORTANCE Mutations of the polymerase complex (PB1, PB2, and PA) of influenza A virus are necessary for viral adaptation to new hosts.This study reports a novel and predominant mammalian adaptive mutation, PA-K356R, in avian H9N2 viruses and human isolates of emergent H7N9 and H10N8 viruses. We found that PA-356R in H9N2 viruses causes significant increases in virus replication and severity of infection in human cells and mice and that PA-K356R cooperates with the PB2-E627K mutation, a wellcharacterized human adaptive marker, to exacerbate mammalian infection in vitro and in vivo. Therefore, the PA-K356R mutation is a significant adaptation in H9N2 viruses and related H7N9 and H10N8 reassortants toward human infectivity. The emergence of new pandemic influenza A viruses requires overcoming barriers to cross-species transmission from animal reservoirs to human populations. Influenza viruses of the H9N2 subtype and their reassortants circulating in poultry are a potential source of pandemic viruses and hence represent a significant public health threat (1). Since spring 2013, a novel avian H7N9 reassortant with six internal genes of the H9N2 virus had caused three major outbreaks in humans throughout China (2, 3). During the same period, a newly emergent avian H10N8 virus, also with six H9N2-like internal genes, was reported to cause fatal human infections in China (4). In the meantime, H9N2 viruses continued to cause human infections in China and other countries based on etiological and serological evidence (5-12). We recently found that avian H9N2 viruses have undergone significant genetic evolution, especially in their internal genes, to form a predominant genotype (G57), which in turn provided the internal genes to multiple new subtypes, including H7N9 and H10N8 viru...

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“…H9N2 AIV is a low pathogenic avian influenza that is widely spread in the poultry farms of China and East Asia. Homology comparisons showed that all six internal genes of the H7N9 and H10N8 influenza viruses that can kill humans are closely related to the H9N2 viruses that are circulating in poultry in China (24)(25)(26)(27)(28). Poultry carrying H9N2 might act as incubators for novel human AIVs (29).…”

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confidence: 99%

Chicken STING Mediates Activation of the IFN Gene Independently of the RIG-I Gene

Cheng

Sun

Wang

et al. 2015

The Journal of Immunology

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Stimulator of IFN genes (STING) is an adaptor that functions downstream of retinoic acid–inducible gene I (RIG-I) in mammalian cells; however, RIG-I is absent in chickens. We identified chicken STING (chSTING) as a critical mediator of virus-triggered type I IFN signaling in RIG-I–null chicken cells. Overexpression of chSTING in DF-1 cells inhibited Newcastle disease virus and avian influenza virus (AIV) viral replication and activated IRF-7 and NF-κB to induce expression of type I IFNs. Knockdown of endogenous chSTING abolished virus-triggered activation of IRF-7 and IFN-β and increased viral yield. chSTING was a critical component in the virus-triggered IRF-7 activation pathway and the cellular antiviral response. chSTING predominantly localized to the outer membrane of the endoplasmic reticulum and was also found in the mitochondrial membrane. Furthermore, knockdown of chSTING blocked polyinosinic-polycytidylic acid–, poly(deoxyadenylic-deoxythymidylic) acid–, and melanoma differentiation–associated gene 5 (MDA5)-stimulated induction of IFN-β. Coimmunoprecipitation experiments indicated that chicken MDA5 could interact with chSTING, and this interaction was enhanced by ectopically expressed chicken mitochondrial antiviral-signaling protein. Together, these results indicated that chSTING is an important regulator of chicken innate immune signaling and might be involved in the MDA5 signaling pathway in chicken cells. These results help with understanding the biological role of STING in innate immunity during evolution.

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Identification of Amino Acid Changes That May Have Been Critical for the Genesis of A(H7N9) Influenza Viruses

Abstract: Novel influenza A viruses of the H7N9 subtype [A(H7N9)]

Cited by 39 publications

References 88 publications

The Nucleoprotein of Newly Emerged H7N9 Influenza A Virus Harbors a Unique Motif Conferring Resistance to Antiviral Human MxA

The Nucleoprotein of Newly Emerged H7N9 Influenza A Virus Harbors a Unique Motif Conferring Resistance to Antiviral Human MxA

Prevailing PA Mutation K356R in Avian Influenza H9N2 Virus Increases Mammalian Replication and Pathogenicity

Chicken STING Mediates Activation of the IFN Gene Independently of the RIG-I Gene

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