Host chaperones can define the fitness of adaptive influenza variants

The threat of viral pandemics demands a comprehensive understanding of evolution at the host-pathogen interface. Here, we systematically show that the accessibility of adaptive mutations in influenza nucleoprotein at fever-like temperatures is mediated by host chaperones. Particularly noteworthy, we observe that the Pro283 nucleoprotein variant, which is conserved across human flu strains, confers resistance to the MxA antiviral-restriction factor, and critically contributed to the pathogenicity of the 1918 pandemic flu, is rendered unfit by host chaperone depletion. This fitness loss is linked to biophysical defects that chaperones cannot address when heat shock factor-I is inhibited. Thus, host chaperones can be hijacked by viruses to un-couple biophysically deleterious consequences of mutations from the benefits of immune escape. In summary, host chaperones play a central role in shaping influenza adaptation, with implications for the evolution of other viruses, for viral host-switching, and for the design of antiviral strategies refractory to resistance. Three replicates each of MDCK cells transduced with inducible inhibitor of HSF1 in the presence or absence of Doxycycline at 37 or 39 degrees C.