Multiple lines of evidence argue that host immune responses are regulated by polymorphic gene networks that are responsible for much of the variation in immune responses seen in genetically diverse populations. The primary objective of this Program is to use genetically diverse mouse models as discovery platforms to identify novel genes and expression networks that regulate immunity and/or promote protective or pathogenic immune outcomes following infection. Our goal is to identify conserved genetic networks that regulate immune responses across pathogens, organ compartments and species, providing high value therapeutic targets for broad-based intervention strategies. To effectively study how variation in polygenic regulatory networks controls immune outcomes, it is necessary to utilize genetic resources that capture large amounts of genetic diversity across the entire genome, allow repeat measures in the same population, exploit existing immune reagents/assays, and are compatible with systems genetics approaches capable of identifying multiple interacting genes. Therefore, we will use the Collaborative Cross (CC), a novel panel of reproducible, recombinant inbred (Rl) mouse lines, to identify genes and gene networks regulating the induction, kinetics, and magnitude of the innate, inflammatory or adaptive immune responses following virus infection, using West Nile Virus, influenza and severe acute respiratory coronavirus (SARS-CoV) as models. Specifically, immune phenotypes will be collected after infection and novel modeling algorithms applied to identify quantitative trait loci (QTL), expression QTL (eQTL), and transcription networks that regulate immune function within and between organs, across virus families, and across species. Causal relationships between natural genetic variation and host signaling networks will be linked with protective or pathologic immune responses and disease outcomes. Our long-term goal is to develop new, genetically defined mouse models to mechanistically dissect the role of specific polymorphic genes and sets of genes in differentially regulating targeted immune responses, including crosstalk between immune components and the development of protective or pathogenic immune responses following virus infection.

Public Health Relevance

We will use the Collaborative Cross, a mouse resource designed to study complex genetic interactions in diverse populations, to identify novel polymorphic genes regulating immune responses to SARS, influenza and West Nile viruses, gain new insights into genetic interactions that shape immune phenotypes in mice and humans, and generate panels of genetically defined mice to probe how sets of polymorphic genes affect immune responses against a variety of pathogens or other immune stimuli.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI100625-02
Application #
8523410
Study Section
Special Emphasis Panel (ZAI1-QV-I (M3))
Program Officer
Chiodetti, Lynda
Project Start
2012-08-05
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$4,030,980
Indirect Cost
$641,217
Name
University of North Carolina Chapel Hill
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Green, Richard; Wilkins, Courtney; Thomas, Sunil et al. (2016) Transcriptional profiles of WNV neurovirulence in a genetically diverse Collaborative Cross population. Genom Data 10:137-140
Morgan, Andrew P; Didion, John P; Doran, Anthony G et al. (2016) Whole Genome Sequence of Two Wild-Derived Mus musculus domesticus Inbred Strains, LEWES/EiJ and ZALENDE/EiJ, with Different Diploid Numbers. G3 (Bethesda) 6:4211-4216
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Zhang, Shuijun; Kostyuchenko, Victor A; Ng, Thiam-Seng et al. (2016) Neutralization mechanism of a highly potent antibody against Zika virus. Nat Commun 7:13679
Graham, Jessica B; Thomas, Sunil; Swarts, Jessica et al. (2015) Genetic diversity in the collaborative cross model recapitulates human West Nile virus disease outcomes. MBio 6:e00493-15
Morgan, Andrew P; Fu, Chen-Ping; Kao, Chia-Yu et al. (2015) The Mouse Universal Genotyping Array: From Substrains to Subspecies. G3 (Bethesda) 6:263-79

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