2. Academic Validation
  3. Host proteostasis modulates influenza evolution

Host proteostasis modulates influenza evolution

  • Elife. 2017 Sep 26;6:e28652. doi: 10.7554/eLife.28652.
Angela M Phillips 1,  Luna O Gonzalez 2,  Emmanuel E Nekongo 1,  Anna I Ponomarenko 1,  Sean M McHugh 3,  Vincent L Butty 4,  Stuart S Levine 4,  Yu-Shan Lin 3,  Leonid A Mirny 5 6,  Matthew D Shoulders 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States.
  • 2 Department of Mathematics, Massachusetts Institute of Technology, Cambridge, United States.
  • 3 Department of Chemistry, Tufts University, Medford, United States.
  • 4 BioMicro Center, Massachusetts Institute of Technology, Cambridge, United States.
  • 5 Department of Physics, Massachusetts Institute of Technology, Cambridge, United States.
  • 6 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, United States.
PMID: 28949290 DOI: 10.7554/eLife.28652
Abstract

Predicting and constraining RNA virus evolution require understanding the molecular factors that define the mutational landscape accessible to these pathogens. RNA viruses typically have high mutation rates, resulting in frequent production of protein variants with compromised biophysical properties. Their evolution is necessarily constrained by the consequent challenge to protein folding and function. We hypothesized that host proteostasis mechanisms may be significant determinants of the fitness of viral protein variants, serving as a critical force shaping viral evolution. Here, we test that hypothesis by propagating influenza in host cells displaying chemically-controlled, divergent proteostasis environments. We find that both the nature of selection on the influenza genome and the accessibility of specific mutational trajectories are significantly impacted by host proteostasis. These findings provide new insights into features of host-pathogen interactions that shape viral evolution, and into the potential design of host proteostasis-targeted Antiviral therapeutics that are refractory to resistance.

Keywords

Hsp90; biochemistry; evolutionary biology; genomics; heat shock factor 1; heat shock response; mutational landscape; none; selection.

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