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Modeling Host Responses to Understand Severe Human Virus Infections


EMSL Project ID
49636

Abstract

This comprehensive and highly integrated systems biology program seeks to delineate the complex host responses that determine the outcome of infections with potentially lethal viruses. To achieve this goal, cells and mice will be infected with wild-type and mutant influenza A, Ebola, and West Nile viruses to collect a variety of sample sets (these activities will be carried out by two Research Projects for influenza and Ebola or West Nile virus, respectively). These research projects will be led by Dr. Yoshihiro Kawaoka at the University of Wisconsin-Madison and Dr. Michael Diamond at Washington University-St. Louis. A Technical Core led by Dr. Richard Smith (Pacific Northwest National Lab; PNNL) will utilize EMSL’s mass spectrometry resources to perform proteomics, lipidomics, and metabolomics profiling, whereas mRNA and miRNA profiling will be out-sourced on a fee-for service basis. In addition, multiple biological datasets, including virological data and data on protein-protein interactions, will be generated. All data will be analyzed by a Computational Modeling Core led by Dr. Katrina Waters (PNNL), which will integrate the diverse datasets and build predictive mechanistic and network models, including virtual lung and liver models. Based on these analyses, the two Research Projects will carry out comprehensive validation studies in vitro and in vivo (i.e., in knock-out mice). OMICs studies (as described above) from virus-infected knock-out and matched wild-type mice will be used for a second round of analysis, thereby achieving the systems biology paradigm of iterative sampling, modeling, and validation. Storage, management, and exchange of the large and diverse datasets, and outreach to the community, will be facilitated by a Data Management and Resources Dissemination Core led by Dr. Miron Livny at UW-Madison, whereas an Administrative Core led by Dr. Kawaoka will ensure that all administrative tasks are addressed. In summary, we propose a comprehensive and interactive systems biology program that will enhance predictive modeling of infectious disease and identify critical regulators of severe human virus pathogenicity that may be exploited for the development of therapeutic interventions.

Project Details

Start Date
2016-10-04
End Date
2019-09-30
Status
Closed

Team

Principal Investigator

Richard Smith
Institution
Pacific Northwest National Laboratory

Team Members

Cameron Casey
Institution
Pacific Northwest National Laboratory

Jennifer Kyle
Institution
Pacific Northwest National Laboratory

Paul Piehowski
Institution
Environmental Molecular Sciences Laboratory

Carrie Nicora
Institution
Pacific Northwest National Laboratory

Kristin Burnum-Johnson
Institution
Environmental Molecular Sciences Laboratory

Thomas Metz
Institution
Pacific Northwest National Laboratory

Related Publications

Burnum-Johnson K.E., X. Zheng, J.N. Dodds, J. Ash, D. Fourches, C.D. Nicora, and J.P. Wendler, et al. 2019. "Ion mobility spectrometry and the omics: Distinguishing isomers, molecular classes and contaminant ions in complex samples." Trends in Analytical Chemistry. TrAC 116. PNNL-SA-140985. doi:10.1016/j.trac.2019.04.022
Couvillion S.P., Y. Zhu, G. Nagy, J.N. Adkins, C.K. Ansong, R.S. Renslow, and P.D. Piehowski, et al. 2018. "New mass spectrometry technologies contributing towards comprehensive and high throughput omics analyses of single cells." Analyst 144, no. 3:794-807. PNNL-SA-137430. doi:10.1039/C8AN01574K
Kyle J.E. 2020. "Extracting Biological Insight from Untargeted Lipidomics Data." In Computation Methods and Data Analysis for Metabolomics. Methods in Molecular Biology, edited by S. Li. 121-137. New York, New York:Humana. PNNL-SA-142580. doi:10.1007/978-1-0716-0239-3_7
Menachery VD, A Schafer, KE Burnum-Johnson, HD Mitchell, AJ Eisfeld-Fenney, KB Walters, CD Nicora, SO Purvine, CP Casey, ME Monroe, KK Weitz, KG Stratton, BJM Webb-Robertson, L Gralinski, TO Metz, RD Smith, KM Waters, AC Sims, Y Kawaoka, and R Baric. 2018. "MERS-CoV and H5N1 influenza virus antagonize antigen presentation by altering the epigenetic landscape." Proceedings of the National Academy of Sciences of the United States of America 115(5):E1012-E1021. doi:10.1073/pnas.1706928115
Nicora C.D., A. Sims, K.J. Bloodsworth, Y. Kim, R.J. Moore, J.E. Kyle, and E.S. Nakayasu, et al. 2020. "Metabolite, Protein, and Lipid Extraction (MPLEx): a method that simultaneously inactivates Middle East respiratory syndrome coronavirus and allows analysis of multiple host cell components following infection." In MERS Coronavirus: Methods and Protocols, edited by R. Vijay. 173-194. New York, New York:Humana. PNNL-SA-142077. doi:10.1007/978-1-0716-0211-9_14