Abstract
The innate-immune restriction factor MxA inhibits influenza replication by targeting the viral nucleoprotein (NP). Human influenza virus is more resistant than avian influenza virus 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 single amino-acid mutations to NP affect MxA sensitivity in the context of replication-competent virus. We both identify new sites in NP where mutations affect MxA resistance and re-identify mutations known to have increased MxA resistance during historical adaptations of influenza to humans. Most of the sites where mutations have the greatest effect are almost completely conserved across all influenza A viruses, and the amino acids at these sites confer relatively high resistance to MxA. These sites cluster in regions of NP that appear to be important for its recognition by MxA. Overall, our work systematically identifies the sites in influenza nucleoprotein where mutations affect sensitivity to MxA. We also demonstrate a powerful new strategy for identifying regions of viral proteins that affect inhibition by host factors.
Highlights
Influenza proteins must evade immunity while maintaining their ability to function and interact with host cell factors [1]
Human cells express proteins that can restrict virus replication. In many cases it remains unclear what determines the sensitivity of a given viral strain to a particular restriction factor
We find several dozen sites where mutations substantially affect the sensitivity of influenza virus to MxA
Summary
Influenza proteins must evade immunity while maintaining their ability to function and interact with host cell factors [1]. The innate immune system exerts selection on influenza virus via the interferonstimulated expression of restriction factors, some of which target viral proteins and inhibit their function. The first anti-influenza restriction factor to be discovered, the murine protein Mx1, was initially described over 50 years ago [6,7,8]. It is known that Mx1 and its human ortholog MxA inhibit influenza virus by interacting with the viral nucleoprotein (NP) [9,10,11,12,13,14]. The exact mechanistic details of the inhibitory interaction between MxA and NP remain incompletely understood
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