Systemic immune responses are regulated by diverse host and pathogen effectors and variation in innate and inflammatory immunity mediate downstream effects on adaptive immune responses. Not surprisingly, a significant range in inter-individual immune responses is noted In humans and mammals, especially in the respiratory tract where virus-immune interactions can be protective or pathogenic. We will identify polygenic immune traits which mediate unique and conserved immune responses, testing the hypothesis that the most significant, highly conserved immune pathways will best be identified in genetically diverse populations that model naturally occurring variation. Thus, we employ the Collaborative Cross (CC), a highly diverse, infinitely reproducible, and customizable recombinant inbred (Rl) mouse panel designed to discover polygenic traits that regulate complex phenotypes, like immunity. The CC captures: a) vast host genetic diversity, b) extreme immune phenotypes, and c) polygenic trait regulation of host immune responses to infection. In Project 1, we use the highly tractable SARS-Coronavirus (SARS-CoV) model to probe immune function in the lung. In the CC, SARS-CoV infection manifests in protective or pathogenic immune phenotypes including diffuse alveolar damage, atypical pneumonia, and acute respiratory distress. Importantly, the SARS-CoV model Is supported by: a) robust genetic, biochemical, immunologic, and virologic tools, b) host immune regulated pathogenic outcomes, c) polygenic traits regulating immune pathways, d) virulence genes which modulate immunity, and e) defined components of protective immunity and clearance.
In Aim 1, we will identify genes and expression networks that regulate the kinetics, composition, and magnitude of innate immunity and inflammation in the lung.
In Aim 2, we identify genes and polygenic networks that regulate the kinetics, magnitude, and effector functions of SARS-CoV specific CDS T cells or the kinetics, avidity, and functional breadth of SARS-CoV specific antibody responses.
In aim 3, we validate the role of genes and polymorphic interactions in unique and conserved immune responses, in immune cross talk, in protective or pathologic disease, and across organs, viruses and host species.

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 that regulate immune responses to SARS-CoV and/or other viruses, provide new insights into how interactions between these genes shape immune phenotypes in mice and humans, and generate panels of genetically defined mice for studying how defined sets of polymorphic genes affect immune responses against a variety of pathogens or rather immune stimuli.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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University of North Carolina Chapel Hill
Chapel Hill
United States
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Menachery, Vineet D; Gralinski, Lisa E; Mitchell, Hugh D et al. (2018) Combination Attenuation Offers Strategy for Live Attenuated Coronavirus Vaccines. J Virol 92:
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Green, Richard; Ireton, Reneé C; Gale Jr, Michael (2018) Interferon-stimulated genes: new platforms and computational approaches. Mamm Genome 29:593-602
Agnihothram, Sudhakar; Menachery, Vineet D; Yount Jr, Boyd L et al. (2018) Development of a Broadly Accessible Venezuelan Equine Encephalitis Virus Replicon Particle Vaccine Platform. J Virol 92:
Johnson, Bryan A; Graham, Rachel L; Menachery, Vineet D (2018) Viral metagenomics, protein structure, and reverse genetics: Key strategies for investigating coronaviruses. Virology 517:30-37

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