Abstract
The adaptation of H5N1 avian influenza viruses to human poses a great threat to public health. Previous studies indicate the adaptive mutations in viral polymerase of avian influenza viruses are major contributors in overcoming the host species barrier, with the majority of mammalian adaptive mutations occurring in the PB2 protein. However, the adaptive mutations in the PA protein of the H5N1 avian influenza virus are less defined and poorly understood. In this study, we identified the synergistic effect of the PA/224P + 383D of H5N1 avian influenza viruses and its ability to enhance the pathogenicity and viral replication in a mammalian mouse model. Interestingly, the signature of PA/224P + 383D mainly exists in mammalian isolates of the H5N1 influenza virus and pdmH1N1 influenza virus, providing a potential pathway for the natural adaptation to mammals which imply the effects of natural adaptation to mammals. Notably, the mutation of PA/383D, which is highly conserved in avian influenza viruses, increases the polymerase activity in both avian and human cells, and may have roles in maintaining the avian influenza virus in their avian reservoirs, and jumping species to infect humans.
Highlights
The highly pathogenic avian influenza (HPAI) H5N1 viruses continue circulation in avian populations results in sporadic infections in humans with a high mortality rate
Our previous study demonstrated that mutations at the residue 224 and 383 in the PA protein greatly contributed to the virulence of H5N1 avian influenza in domestic ducks[35], which is one of avian influenza virus’s natural reservoirs
We identified mutations at both position 224 and 383 in the PA protein significantly altered the pathogenicity and viral replication of avian H5N1 viruses in mice
Summary
The highly pathogenic avian influenza (HPAI) H5N1 viruses continue circulation in avian populations results in sporadic infections in humans with a high mortality rate. Previous studies have demonstrated that multiple viral components play a role in pathogenicity and adaptation of the avian influenza virus in mammals. Et al demonstrated that two amino acid residues in the matrix protein M1 contribute to differences in virulence of the H5N1 viruses in mice[16]. E627K and D701N are two well-characterized mutations of the PB2 protein that are critical for mammalian adaptation of multiple subtypes of the avian influenza viruses[3,4,5,19,27,28]. Most mammalian adaptive mutations in the polymerase of avian influenza virus are correlated with enhanced polymerase activity in mammalian cells[19,20,23,24,30,37] so we tested the contribution of residue 224 and 383 to viral polymerase activity in both human and avian cells. We analyzed the polymorphisms of the residues PA/224 and PA/383 in natural isolates of influenza viruses
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