Key Role of the Influenza A Virus PA Gene Segment in the Emergence of Pandemic Viruses

Lutz, Michael M.; Dunagan, Megan M; Kurebayashi, Yoichi; Takimoto, Toru

doi:10.3390/v12040365

Cited by 21 publications

(18 citation statements)

References 128 publications

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“…Alternatively, the three PA mutations identified in this study may alter polymerase activity by interacting with cellular host factors since they were all exposed on the polymerase surface. Collectively, these results reinforced the hypothesis that adaptive PA mutations may have multiple functions in expanding the viral host range ( 35 ). At present, the exact mechanism(s) by which PA mutations enhance polymerase activity remains unknown, and further investigation is needed.…”

Section: Discussionsupporting

confidence: 73%

“…Adaptive mutations and/or reassortments in the avian influenza virus polymerase complex are major factors enabling the virus to overcome the species barrier between birds and humans ( 2 , 7 , 34 ). The avian PB1 polymerase subunit can function in human cells when combined with human-adapted PB2 and PA polymerase subunits ( 35 ). This was observed in the 1957 and 1968 pandemic viruses that contained an avian PB1 gene combined with PB2 and PA genes from human-adapted viruses ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has become apparent that PA plays a role in the host adaptation of AI viruses ( 35 , 38 ), with mutations identified throughout the PA gene sequence (i.e., A36T, S37A, T85I, G186S, L336M, A343S/T, K356R, N383D, and N409S) ( 19 , 20 , 22 , 39 – 43 ). These mutations imply that PA plays multiple roles in AI virus adaptation.…”

Section: Discussionmentioning

confidence: 99%

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PA Mutations Inherited during Viral Evolution Act Cooperatively To Increase Replication of Contemporary H5N1 Influenza Virus with an Expanded Host Range

Arai

Kawashita

Elgendy

et al. 2020

J Virol

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Adaptive mutations and/or reassortments in avian influenza virus polymerase subunits PA, PB1 and PB2 are one of the major factors enabling the virus to overcome the species barrier to infect humans. The majority of human-adaptation polymerase mutations have been identified in PB2: fewer adaptation mutations have been characterized in PA and PB1. Clade 2.2.1 avian influenza viruses (H5N1) are unique to Egypt and generally carry the human-adaptation PB2-E627K substitution during their dissemination in nature. In this study, we identified other human-adaptation polymerase mutations by analyzing phylogeny-associated PA mutations that H5N1 clade 2.2.1 viruses have accumulated during their evolution in the field. This analysis identified several PA mutations that produced increased replication by contemporary clade 2.2.1.2 viruses in vitro in human cells and in vivo in mice compared to ancestral clade 2.2.1 viruses. The PA mutations acted cooperatively to increase viral polymerase activity and replication both in avian and human cells, with the effect more prominent in human cells at 33°C than at 37°C. These results indicated that PA mutations have a role in establishing contemporary clade 2.2.1.2 virus infections in poultry and in adaptation to infect mammals. Our study provided data on the mechanism for PA mutations to accumulate during avian influenza virus evolution and extend the viral host range. IMPORTANCE Clade 2.2.1 avian influenza viruses (H5N1) are unique to Egypt and have caused the highest number of human H5N1 influenza cases worldwide, presenting a serious global public health threat. These viruses may have the greatest evolutionary potential for adaptation from avian hosts to human hosts. Using a comprehensive phylogenetic approach, we identified several novel clade 2.2.1 virus polymerase mutations that increased viral replication in vitro in human cells and in vivo in mice. These mutations were in the polymerase PA subunit and acted cooperatively with the E627K mutation in the PB2 polymerase subunit to provide higher replication in contemporary clade 2.2.1.2 viruses than in ancestral clade 2.2.1 viruses. These data indicated that ongoing clade 2.2.1 dissemination in the field has driven PA mutations to modify viral replication to enable host range expansion, with higher public health risk for humans.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

PA Mutations Inherited during Viral Evolution Act Cooperatively To Increase Replication of Contemporary H5N1 Influenza Virus with an Expanded Host Range

Arai

Kawashita

Elgendy

et al. 2020

J Virol

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“…Influenza A viruses are enveloped RNA viruses with a viral genome (1) consisting of eight segmented negative-sense single-stranded RNAs encoding 10 core proteins known as Polymerase basic 2 (PB2), Polymerase basic 1 (PB1), Polymerase acidic (PA), Hemagglutinin (HA), Nucleoprotein (NP), Neuraminidase (NA), Matrix proteins (M1 and M2) and non-structural proteins (NS1 and NS2) and some other functional accessory proteins, such as Polymerase basic 1-F2 (PB1-F2), Polymerase basic 1 N40 (PB1N40), Polymerase acidic-X (PA-X), et al (2)(3)(4)(5)(6)(7)(8). The polymerase tripartite complex consisting of PB1, PB2 and PA forms an RNA ribonucleoprotein (RNP) with the viral RNA and NP protein (9), which is responsible for the transcription and replication of the viral RNAs (10).…”

Section: Introductionmentioning

confidence: 99%

Advances in Development and Application of Influenza Vaccines

et al. 2021

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Influenza A virus is one of the most important zoonotic pathogens that can cause severe symptoms and has the potential to cause high number of deaths and great economic loss. Vaccination is still the best option to prevent influenza virus infection. Different types of influenza vaccines, including live attenuated virus vaccines, inactivated whole virus vaccines, virosome vaccines, split-virion vaccines and subunit vaccines have been developed. However, they have several limitations, such as the relatively high manufacturing cost and long production time, moderate efficacy of some of the vaccines in certain populations, and lack of cross-reactivity. These are some of the problems that need to be solved. Here, we summarized recent advances in the development and application of different types of influenza vaccines, including the recent development of viral vectored influenza vaccines. We also described the construction of other vaccines that are based on recombinant influenza viruses as viral vectors. Information provided in this review article might lead to the development of safe and highly effective novel influenza vaccines.

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“…Host-adaptive mutations that IAV undergoes make it easily adaptable to a new host, thereby restoring their full activity as described by Chen et al [ 23 ]. This issue is highlighted very nicely by Lutz IV et al in their review [ 24 ], where they have focused on the polymerase gene PA and the ease with which host adaptive mutations occur in it. Interestingly the PA-X protein that is expressed from within the PA gene is believed to have immunomodulatory functions and is quite conserved amongst many IAV strains; but its activity varies between viruses specific for different hosts, suggesting that PA-X may have a role in host adaptation.…”

mentioning

confidence: 99%