Comparative evolution of influenza A virus H1 and H3 head and stalk domains across host species

Abstract

ABSTRACT The influenza A virus hemagglutinin protein (HA) has been studied extensively in humans but less so in other host species. Here, we compared the rates of nucleotide substitution, protein evolution, and glycosylation in the H1 and H3 head and stalk domains among five host classes (avian, canine, equine, human, and swine). For further resolution, we separately analyzed 49 lineages differentiated by host and geography. HA evolution in non-human hosts was more dynamic than expected. For example, the classical swine H1 head domain accumulated glycosylation sites in the antigenically important head domain at a rate as high as in humans. However, whereas the stalk domain was highly conserved in humans, with a low ratio of non-synonymous to synonymous changes, this ratio was approximately 2.5-fold higher in canines. Together, these findings highlight the need for further study of HA evolution in non-human hosts. IMPORTANCE For decades, researchers have studied the rapid evolution of influenza A viruses for vaccine design and as a useful model system for the study of host/parasite evolution. By performing an exhaustive analysis of hemagglutinin protein (HA) sequences from 49 lineages independently evolving in birds, swine, canines, equines, and humans over the last century, our work uncovers surprising features of HA evolution. In particular, the canine H3 stalk, unlike human H3 and H1 stalk domains, is not evolving slowly, suggesting that evolution in the stalk domain is not universally constrained across all host species. Therefore, a broader multi-host perspective on HA evolution may be useful during the evaluation and design of stalk-targeted vaccine candidates.