Growth of H5N1 Influenza A Viruses in the Upper Respiratory Tracts of Mice

Top Cited Papers
Open Access
Publisher Website
Google Scholar
Abstract
Highly pathogenic avian H5N1 influenza A viruses have spread throughout Asia, Europe, and Africa, raising serious worldwide concern about their pandemic potential. Although more than 250 people have been infected with these viruses, with a consequent high rate of mortality, the molecular mechanisms responsible for the efficient transmission of H5N1 viruses among humans remain elusive. We used a mouse model to examine the role of the amino acid at position 627 of the PB2 viral protein in efficient replication of H5N1 viruses in the mammalian respiratory tract. Viruses possessing Lys at position 627 of PB2 replicated efficiently in lungs and nasal turbinates, as well as in cells, even at the lower temperature of 33 °C. Those viruses possessing Glu at this position replicated less well in nasal turbinates than in lungs, and less well in cells at the lower temperature. These results suggest that Lys at PB2–627 confers to avian H5N1 viruses the advantage of efficient growth in the upper and lower respiratory tracts of mammals. Therefore, efficient viral growth in the upper respiratory tract may provide a platform for the adaptation of avian H5N1 influenza viruses to humans and for efficient person-to-person virus transmission, in the context of changes in other viral properties including specificity for human (sialic acid α-2,6-galactose containing) receptors. Highly pathogenic avian H5N1 influenza A viruses have spread around the world since 2003, raising serious worldwide concern about their pandemic potential. Although efficient human-to-human transmission of this virus has not yet occurred, the potential of these viruses to acquire the ability is evident. The receptor specificity of the haemmaglutinin (HA) protein is considered a main factor affecting efficient transmission of H5N1 viruses. Yet, some H5N1 viruses isolated from humans that possess human receptor specificity have still failed to spread efficiently among humans. Therefore, amino acid substitutions in viral proteins other than the receptor-binding HA protein must be necessary for efficient growth and person-to-person transmission of avian H5N1 influenza virus. In our study, we defined the contribution of the amino acid at position 627 of the PB2 to efficient replication of H5N1 influenza viruses in the upper respiratory tracts of mice as a mammalian model. Because efficient viral growth in the upper respiratory tract of humans can facilitate virus excretion by coughing and sneezing, a mutation of PB2 amino acid 627, which contributes to efficient growth at this site in a mammal, may be prerequisite for efficient human-to-human transmission.