Comprehensive mapping of avian influenza polymerase adaptation to the human host

Abstract

Viruses like influenza are infamous for their ability to adapt to new hosts. Retrospective studies of natural zoonoses and passaging in the lab have identified a modest number of host-adaptive mutations. However, it is unclear if these mutations represent all ways that influenza can adapt to a new host. Here we take a prospective approach to this question by completely mapping amino-acid mutations to the avian influenza virus polymerase protein PB2 that enhance growth in human cells. We identify numerous previously uncharacterized human-adaptive mutations. These mutations cluster on PB2's surface, highlighting potential interfaces with host factors. Some previously uncharacterized adaptive mutations occur in avian-to-human transmission of H7N9 influenza, showing their importance for natural virus evolution. But other adaptive mutations do not occur in nature because they are inaccessible via single-nucleotide mutations. Overall, our work shows how selection at key molecular surfaces combines with evolutionary accessibility to shape viral host adaptation.

Joint visualization of seasonal influenza serology and phylogeny to inform vaccine composition

“…The data structure for the measurements panel is purposefully agnostic to the pathogen or data generation approach. As research continues on the emergence of human pathogens from natural reservoirs in other organisms (Leendertz et al, 2016;Olival et al, 2017) and high-dimensional experimental measurements of these pathogens accumulate (Soh et al, 2019;Starr et al, 2022), this flexible data structure and the resulting interactive visualizations could impact decision-making related to pandemic preparedness.…”

Mammalian cells use the autophagy process to restrict avian influenza virus replication

“…Influenza virus serves as an ideal model for studying virus host interactions because it is one of the few RNA viruses that infects multiple hosts and replicates in the nucleus of infected cells, providing opportunities for dissecting host barriers and virusadaptive strategies throughout multiple stages of the virus life cycle. An excellent example is the multiple adaptive mutations acquired by different influenza viruses within the polymerase PB2 subunit, which optimize replication in mammalian cells (Soh et al, 2019;Song et al, 2014). Adaptive mutations in NP and other polymerase subunits also occur, as the viral polymerase functions as a complex (Chen et al, 2006a).…”

“…Multiple adaptation markers in the polymerase subunits, nucleoprotein, and non-structural proteins have been identified in various influenza viruses causing human infections. Among all known host-adaptive substitutions, mutations in the PB2 subunit are the most commonly found and extensively studied (Huang et al, 2017;Mä nz et al, 2012;Mehle and Doudna, 2009;Naffakh et al, 2008;Soh et al, 2019;Song et al, 2014;Subbarao et al, 1993;Yamada et al, 2010).…”