Abstract
The threat of viral pandemics demands a comprehensive understanding of evolution at the host–pathogen interface. Here, we 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 (1) is conserved across human influenza strains, (2) confers resistance to the Myxovirus resistance protein A (MxA) restriction factor, and (3) critically contributed to adaptation to humans in the 1918 pandemic influenza strain, is rendered unfit by heat shock factor 1 inhibition–mediated host chaperone depletion at febrile temperatures. This fitness loss is due to biophysical defects that chaperones are unavailable to address when heat shock factor 1 is inhibited. Thus, influenza subverts host chaperones to uncouple the biophysically deleterious consequences of viral protein variants from the benefits of immune escape. In summary, host proteostasis plays a central role in shaping influenza adaptation, with implications for the evolution of other viruses, for viral host switching, and for antiviral drug development.
Highlights
RNA viruses are exceptionally efficient pathogens that leverage host machineries to replicate their genetic material, synthesize their proteins, and assemble new virions
Host protein folding factors called chaperones interact extensively with viral proteins, like influenza nucleoprotein, and are poised to potentiate the fitness of biophysically defective, adaptive variants. We directly test this hypothesis by quantitatively profiling the mutational tolerance of influenza nucleoprotein in host cells with reduced chaperone levels
We employed previously reported duplicate NP mutant libraries based on the human-adapted A/Aichi/2/1968 (H3N2) influenza strain [24] and competed each viral library in Madin Darby canine kidney (MDCK) cells
Summary
RNA viruses are exceptionally efficient pathogens that leverage host machineries to replicate their genetic material, synthesize their proteins, and assemble new virions. Perhaps their most remarkable feature, is the capacity to rapidly evolve in the face of environmental and immune system pressures. Such rapid evolution is largely mediated by a high mutation rate [1]. The human restriction factor Myxovirus resistance protein A (MxA) can prevent influenza ribonucleoprotein import [11,12,13], cutting short the viral replication cycle
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