Hijacking the Host Cell's Protein Homeostasis Network to Potentiate Influenza Evolution

Successful viral evolution hinges on the efficient sampling of protein sequences. This sampling permits the fixation of adaptive mutations, enabling evasion of immune responses and antiviral therapeutics. 1 Often, these mutations are destabilizing to the proteins in which they occur. Yet mutation propagation demands that the new, mutant viral proteins are correctly folded and functional so the virus can survive. Most viruses are minimalistic, lacking autonomous chaperones to facilitate protein folding and resolve this problem. It is known that certain viral proteins, such as influenza RNA polymerase, leverage host chaperones to assist their assembly. 2 However, it is unknown how viral evolutionary capacity is influenced by the composition and activities of the host cell's protein homeostasis network. We hypothesize that viruses hijack the host cell's protein‐folding machinery to help fold their own proteins and will therefore be better able to accumulate destabilizing mutations when more host chaperones are present. We are testing this hypothesis by serially passaging influenza A in cells with distinct protein‐folding environments and quantifying the accumulation of mutations using next generation sequencing methods. Our early efforts suggest that influenza evolution is influenced by the host's protein‐folding environment, which could aid in the identification of novel antiviral targets. This project is funded by the Smith Family Foundation.