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

Michael M. Lutz,Toru Takimoto,Megan M. Dunagan,Yuki Kurebayashi

doi:10.3390/v12040365

Abstract

Influenza A viruses (IAVs) are a significant human pathogen that cause seasonal epidemics and occasional pandemics. Avian waterfowl are the natural reservoir of IAVs, but a wide range of species can serve as hosts. Most IAV strains are adapted to one host species and avian strains of IAV replicate poorly in most mammalian hosts. Importantly, IAV polymerases from avian strains function poorly in mammalian cells but host adaptive mutations can restore activity. The 2009 pandemic H1N1 (H1N1pdm09) virus acquired multiple mutations in the PA gene that activated polymerase activity in mammalian cells, even in the absence of previously identified host adaptive mutations in other polymerase genes. These mutations in PA localize within different regions of the protein suggesting multiple mechanisms exist to activate polymerase activity. Additionally, an immunomodulatory protein, PA-X, is expressed from the PA gene segment. PA-X expression is conserved amongst many IAV strains but activity varies between viruses specific for different hosts, suggesting that PA-X also plays a role in host adaptation. Here, we review the role of PA in the emergence of currently circulating H1N1pdm09 viruses and the most recent studies of host adaptive mutations in the PA gene that modulate polymerase activity and PA-X function.

Highlights

The frameshift motif is highly conserved amongst Influenza A viruses (IAVs), suggesting that PA-X is essential for the viral life cycle [88]
While PB2 has traditionally been viewed as the major determinant for restriction of avian vRdRp activity in mammalian cells, recent studies on the H1N1pdm09 virus and avian IAVs, such as H5N1 and H7N9, found that PA plays an important role too
It is notable that many of the observed host adaptive mutations in PA are located within the endonuclease domain, which plays a critical role in the viral life cycle during both viral mRNA transcription and PA-X shutoff activity

Summary

Influenza A Viruses

Influenza A viruses (IAVs) are members of the Orthomyxoviridae family of RNA viruses and are capable of infecting a wide array of species. IAV is classified into different subtypes dependent on two viral glycoproteins, hemagglutinin (HA) and neuraminidase (NA) [1]. Avian species such as waterfowl are the natural host reservoir of IAVs where 16 HA subtypes and 9 NA subtypes have been observed to circulate; in addition, two subtypes H17N10 and H18N11 have been observed in bats [2,3]. Most strains of IAV are adapted to one host species, but genomic reassortment between human and avian viruses has previously led to pandemic outbreaks. In order to cross the species barrier, these avian IAVs need to acquire adaptive mutations in certain viral genes [4]. RNA-dependent RNA polymerase (vRdRp) has been identified as a significant factor regulating the host adaptation of avian IAVs to mammals

The Influenza A Virus RNA-Dependent RNA Polymerase

Host Adaptive Mutations in Polymerase Proteins

Structural and Functional Domains of PA

Contribution of Mutations in PA to Host Adaptation

Structure

Additional Proteins Expressed from the PA Gene Segment

Host Shutoff Activity of Influenza A Virus

Structural and Functional Domains of PA-X

Structure the IAV

Mechanism of Host mRNA Degradation by PA-X

Impact of PA-X on Influenza A Virus Pathogenicity

Clinical Interventions Targeting PA