Deep mutational scanning identifies sites in influenza nucleoprotein that affect viral inhibition by MxA

The innate-immune restriction factor MxA inhibits influenza replication by targeting the viral nucleoprotein (NP). Human influenza is more resistant than avian influenza to inhibition by human MxA, and prior work has compared human and avian viral strains to identify amino-acid differences in NP that affect sensitivity to MxA. However, this strategy is limited to identifying sites in NP where mutations that affect MxA sensitivity have fixed during the small number of documented zoonotic transmissions of influenza to humans. Here we use an unbiased deep mutational scanning approach to quantify how all {approx}10,000 amino-acid mutations to NP affect MxA sensitivity. We both identify new sites