Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones

by Angela M. Phillips, Anna I. Ponomarenko, Kenny Chen, Orr Ashenberg, Jiayuan Miao, Sean M. McHugh, Vincent L. Butty, Charles A. Whittaker, Christopher L. Moore, Jesse D. Bloom, Yu-Shan Lin, Matthew D. Shoulders

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.

Source link

Related posts

Loss of MYO5B expression deregulates late endosome size which hinders mitotic spindle orientation


molecular biology; +279 new citations


Cross-linker-mediated regulation of actin network organization controls tissue morphogenesis


This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out if you wish. Accept Read More

Privacy & Cookies Policy