Host proteostasis modulates influenza evolution

eLife

Matthew D Shoulders¹  Stuart S Levine²  Vincent L Butty²  Anna I Ponomarenko³  Emmanuel E Nekongo³  Angela M Phillips³  Yu-Shan Lin⁴  Sean M McHugh⁴  Luna O Gonzalez⁵  Leonid A Mirny⁶ 

[1] Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, United States;BioMicro Center, Massachusetts Institute of Technology, Cambridge, United States;Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States;Department of Chemistry, Tufts University, Medford, United States;Department of Mathematics, Massachusetts Institute of Technology, Cambridge, United States;Department of Physics, Massachusetts Institute of Technology, Cambridge, United States;

关键词: heat shock response;    Hsp90;    mutational landscape;    selection;    heat shock factor 1;   

DOI  :  10.7554/eLife.28652

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown