Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones
Name
journal.pbio.3000008.pdf
Description
Published version
Size
3.33 MB
Format
Adobe PDF
Checksum (MD5)
1deafeda128e0f9175949e9260ff121e
Author(s)
Phillips, Angela Marie
Ponomarenko, Anna
Butty, Vincent L G
Whittaker, Charles A.
Moore, Christopher Lawrence
Shoulders, Matthew D.
Chen, Kenny,Ph. D.Massachusetts Institute of Technology.
Date Issued
September 2018
Journal
PLoS biology
Publisher
Public Library of Science (PLoS)
Citation
Phillips, Angela M. et al. “Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones.” PLoS biology 16 (2018): e3000008 © 2018 The Author(s)
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1371/JOURNAL.PBIO.3000008
