Crucial role of PA in virus life cycle and host adaptation of influenza A virus

Hu, Jiao; Liu, Xiufan

doi:10.1007/s00430-014-0349-y

Cited by 17 publications

(11 citation statements)

References 151 publications

(128 reference statements)

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“…Adaptive mutations in PA proteins of AIVs are recognized as being crucial for cross-species transmission to mammals (35). In the present study, we characterized and compared one such adaptive mutation, PA-K356R, in an avian H9N2 virus, which promoted PA nuclear accumulation and viral polymerase activity in mam- Lower limits of detection were 10 1.25 TCID 50 /ml for nasal turbinates or lungs.…”

Section: Discussionmentioning

confidence: 95%

“…The functions of the PA protein are associated with its interactions with the PB1 and PB2 proteins and with its endonuclease and protease activities (35). It can be cleaved by limited tryptic digestion into N-terminal (PA-N) and C-terminal (PA-C) domains (36).…”

Section: Figmentioning

confidence: 99%

“…It can be cleaved by limited tryptic digestion into N-terminal (PA-N) and C-terminal (PA-C) domains (36). Known mammalian adaptive mutations are found mainly in the PA-N region (35), with some being found in the PA-C domain, such as PA-T552S in human isolates (25,37). PA-356 is located in the PA-C domain and is close to the loop spanning amino acid positions 350 to 355 (i.e., the 350 -355 loop) (38).…”

Section: Figmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 95%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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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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“…Of the three RdRp subunits, PB1 and PB2 are responsible for viral RNA synthesis and binding to the cap structure of cellular-capped RNA (required for the initiation of viral transcription), respectively, whereas PA has multiple roles, such as cleavage of the capped RNA 11 and serine proteinase activities 12 . Lack of PA protein expression in a reverse genetics system led to no recovery of recombinant influenza virus 13 , thereby suggesting that PA has crucial roles in the virus life cycle 14 . PA interacts with PB1 and PB1 interacts with PB2 according to crystal structure analyses 15 – 17 .…”

Section: Introductionmentioning

confidence: 99%

Structure-based drug discovery for combating influenza virus by targeting the PA–PB1 interaction

Watanabe

Ishikawa

Otaki

et al. 2017

Sci Rep

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Influenza virus infections are serious public health concerns throughout the world. The development of compounds with novel mechanisms of action is urgently required due to the emergence of viruses with resistance to the currently-approved anti-influenza viral drugs. We performed in silico screening using a structure-based drug discovery algorithm called Nagasaki University Docking Engine (NUDE), which is optimised for a GPU-based supercomputer (DEstination for Gpu Intensive MAchine; DEGIMA), by targeting influenza viral PA protein. The compounds selected by NUDE were tested for anti-influenza virus activity using a cell-based assay. The most potent compound, designated as PA-49, is a medium-sized quinolinone derivative bearing a tetrazole moiety, and it inhibited the replication of influenza virus A/WSN/33 at a half maximal inhibitory concentration of 0.47 μM. PA-49 has the ability to bind PA and its anti-influenza activity was promising against various influenza strains, including a clinical isolate of A(H1N1)pdm09 and type B viruses. The docking simulation suggested that PA-49 interrupts the PA–PB1 interface where important amino acids are mostly conserved in the virus strains tested, suggesting the strain independent utility. Because our NUDE/DEGIMA system is rapid and efficient, it may help effective drug discovery against the influenza virus and other emerging viruses.

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“…The host restriction of influenza A virus significantly reduces the possibility of cross‐species transmission, which is a great threat to public health, although viruses acquire this ability by accumulating mutations, and once the virus is adapted to a new host, an epidemic might break out . There are a number of factors involved in influenza virus host adaptation , of which the polymerase basic protein 2 (PB2) 627 is an important viral factor , although the mechanism is not fully understood. Adaptation to a mammalian host commonly occurs when the PB2 627 site of avian influenza virus mutates from glutamic acid (E) to lysine (K); therefore, the PB2 E627K mutation is a marker of avian influenza virus adaptation for mammalian hosts.…”

Section: Introductionmentioning

confidence: 99%

Evidence for a novel mechanism of influenza A virus host adaptation modulated by PB2‐627

et al. 2019

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Influenza virus cross‐species transmission is restricted by the host, but viruses overcome this restriction by accumulating mutations which allow them to adapt to a new host. Among the many factors which facilitate virus host adaptation, polymerase basic protein 2 (PB2) 627 plays an important role, although the underlying molecular mechanism has not been fully understood. In a previous study, we found that histone H1.2 (encoded by HIST1H1C) regulates human or avian influenza virus replication in different ways, indicating that it might be involved in virus host adaptation. Herein, we found that HIST1H1C expression, phosphorylation and methylation levels are decreased when infected with H1N1 influenza virus and increased when infected with H5N1 influenza virus. Overexpressing the eight gene segments of the influenza virus, we found that only PB2 significantly affects HIST1H1C expression and modifications. Since the 627 site is different between the H5N1 and H1N1 influenza viruses we constructed PB2‐627E (avian variant) and PB2‐627K (human variant) mutant viruses, and observed that the effects of the wild‐type and the mutant viruses on HIST1H1C expression and modifications are the opposite of one another. Further analysis showed that influenza virus PB2‐627 regulates HIST1H1C expression via Sp1, and specifically that PB2‐627K down‐regulates Sp1 and HIST1H1C while PB2‐627E up‐regulates Sp1 and HIST1H1C. In addition, HIST1H1C can feedback regulate DNA‐dependent protein kinase and euchromatic histone‐lysine N‐methyltransferase 1/2, leading to altered HIST1H1C phosphorylation and methylation levels, and affecting influenza virus replication accordingly. In summary, this study illustrates the mechanism of PB2‐627E/K‐mediated regulation of influenza virus host adaptation.

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Crucial role of PA in virus life cycle and host adaptation of influenza A virus

Cited by 17 publications

References 151 publications

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

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

Structure-based drug discovery for combating influenza virus by targeting the PA–PB1 interaction

Evidence for a novel mechanism of influenza A virus host adaptation modulated by PB2‐627

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