In this study, we aim to functionally Interrogate host-pathogen relationships using three different enteroviruses (poliovirus, EV71 and coxsackievirus). To this end, we will use a variety of methods to systematically generate viral-host protein-protein and genetic interaction maps. The data generated using these initial, unbiased approaches will fuel more targeted, hypothesis-driven research in the subsequent projects. Although we intend to follow up on the most Interesting, unanticipated connections we uncover, we will be closely monitoring for links to host factors involved in quality control processes, including chaperone function, protein ubiquitination and protein degradation, which will link this work to the work described in Projects 2 and 3. In collaboration with Sumit Chanda (Burnham Institute) and John Young (Salk Institute), we will utilize RNAI methodology to globally assess the genetic dependencies, both positive and negative, of host factors to the pathogenesis of the three enteroviruses (Aim 1). Next, to characterize the enterovlrus-human protein-protein interactions, we intend to collaborate with Al Burlingame (UCSF) to employ a systematic affinity tag/purlflcation-mass spectrometry approach to Identify the viral-host protein complexes (Aim 2). We also Intend to globally ascertain the effects of protein post-translational modifications upon infection using mass spectrometry (Aim 3). Finally, In Aim 4, we will utilize a suite of bioinformatic and visualization tools to integrate the data sets in a meaningful fashion so that specific hypotheses regarding quality control processes can be generated and tested in collaboration with Judith Frydman (Project 2) and Raul Andino (Project 3). This integrated approach will leverage the expertise from multiple groups, including Pis of the Technology Core (Andrej Sali and Joe Derisi), so that novel host pathways that are hijacked during Infection can be Identified and characterized. This information will hopefully lead to breakthroughs with anti-viral drugs and vaccines.

Public Health Relevance

Human enteroviruses Infect millions of people worldwide each year, resulting in a wide range of clinical outcomes ranging from respiratory illness to meningitis. To gain insight Into the pathogenesis of these viruses, we aim to analyze the functional, genetic and biochemical relationships between several members of this class of virus and host cells, which will reveal key human pathways that are being hijacked during infection. This information can ultimately be used to generate novel anti-viral drugs and vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI091575-03
Application #
8501344
Study Section
Special Emphasis Panel (ZAI1-BB-M)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$338,496
Indirect Cost
$94,913
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Webb, Benjamin; Sali, Andrej (2016) Comparative Protein Structure Modeling Using MODELLER. Curr Protoc Bioinformatics 54:5.6.1-5.6.37
Xiao, Yinghong; Rouzine, Igor M; Bianco, Simone et al. (2016) RNA Recombination Enhances Adaptability and Is Required for Virus Spread and Virulence. Cell Host Microbe 19:493-503
Cimermancic, Peter; Weinkam, Patrick; Rettenmaier, T Justin et al. (2016) CryptoSite: Expanding the Druggable Proteome by Characterization and Prediction of Cryptic Binding Sites. J Mol Biol 428:709-719

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