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

PLoS Biology
Angela M PhillipsMatthew D Shoulders

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.

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Citations

Mar 13, 2019·Cold Spring Harbor Perspectives in Biology·Ranen Aviner, Judith Frydman
Feb 26, 2020·Annual Review of Biochemistry·Rebecca M Sebastian, Matthew D Shoulders
Sep 27, 2018·Nature Reviews. Microbiology·Andrea Du Toit
Jun 6, 2020·ACS Infectious Diseases·Emmanuel E NekongoMatthew D Shoulders

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Methods Mentioned

BETA
protein folding
circular dichroism
transfection
Assay
RosettaCM
RNA-seq
size exclusion chromatography
PCR

Software Mentioned

samtools mpileup
samtools
GraphPad Prism
dms
RosettaCM
bwa mem
DESeq2
multcomp R package
R
STAR

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