Host proteostasis modulates influenza evolution

Author:

Phillips Angela M1ORCID,Gonzalez Luna O2,Nekongo Emmanuel E1,Ponomarenko Anna I1,McHugh Sean M3,Butty Vincent L4,Levine Stuart S4,Lin Yu-Shan3ORCID,Mirny Leonid A56ORCID,Shoulders Matthew D1ORCID

Affiliation:

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

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.

Funder

National Science Foundation

Richard and Susan Smith Family Foundation

National Institutes of Health

Merck

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

Reference95 articles.

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