The high mutation rates of enteroviruses are essential for their adaptability and pathogenesis. These virus populations do not have a single identical sequence, but rather exist as quasispecies, i.e. clouds of virus with related sequences. Mutations accumulated during virus replication may lead to the destabilization of proteins and Increase their tendency to misfold and aggregate. Molecular chaperones, which promote protein folding and protect the proteome from stress and misfolding, are proposed to buffer detrimental mutations, by restoring the proper conformation of destabilized proteins. Chaperones also communicate with the Ubiquifin Proteasome System (UPS) protein to ensure correct Quality Control (QC) of damaged proteins. Enteroviruses are completely dependent on the cellular chaperone and QC machinery for their protein production and function. Given the very high mutation rates of these viruses, we hypothesize that chaperones and QC components are key to modulating virus diversity, evolution and pathogenesis. Central to our hypothesis Is the idea that viral protein stability is a major constrain on virus evolution and sequence diversity. We propose that chaperones keep viral mutant proteins functional while QC pathways clear nonfunctional dominant negative mutants. This project will examine how these processes modulate the poliovirus, EV71 and coxsakievirus B6 sequence space and viral adaptability. To accomplish this, we will perturb specific components of the protein homeostasis machinery and determine the consequences on population diversity, evolution and pathogenesis.

Public Health Relevance

Enteroviruses have been associated with many clinically recognized, life-threatening syndromes. Virus evolution is at the core of virus drug resistant, immunological survey escape and pathogenesis. Understanding protein homeostasis will illuminate the rules that govern virus diversity, evolution and pathogenesis, and it may allow the development of safe and effective vaccines and anti-enterovirus drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI091575-04
Application #
8690750
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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