Implications of localized charge for human influenza A H1N1 hemagglutinin evolution: Insights from deep mutational scans

摘要

The hemagglutinin (HA) surface protein of influenza A viruses evolves rapidly to evade host immunity, leading to sizable yearly epidemics in human populations. Previous transmission experiments with H1N1 in mice have tied immune escape to an increase in HA avidity for cellular receptors, mediated by electrostatic charge. Furthermore, retrospective sequence analyses from a previous study confirmed that the HA of circulating global H3N2 has increased in net charge, yet surprisingly, that of H1N1 has not varied significantly. How is a stable net charge related to local patterns of H1N1 HA charge in response to selection? To elucidate the role of local electrostatic charge in host-virus interactions, we investigate characteristics of local charge on the H1N1 HA using functional data from deep mutational scan experiments. Combining measures of functional selection and expected charge at each site on DMS data from a 1933 H1N1 HA yields a striking visual pattern that identifies three groups of sites that have different biophysical properties and that prove to have distinct evolutionary patterns in natural human sequences. Essentially, we find evidence for an increase in charge near the receptor binding site and for compensatory changes elsewhere on the protein. Thus, our findings may reconcile disparate results from transmission experiments and natural sequence analyses, and highlight the importance of local properties of the HA protein. Overall, our findings further support the hypothesis of immune escape due to increased HA avidity to cellular receptors mediated by electrostatic charge. More generally, our work illustrates a novel method of leveraging deep mutational scans in conjunction with natural sequences to shed light on virus-host interactions.