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 surprsingly, 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 seta of polymorphic genes affect immune responses against a variety of pathogens or rather immune stimuli.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI100625-03
Application #
8706027
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
Ferris, Martin T; Heise, Mark T (2014) Quantitative genetics in the study of virus-induced disease. Adv Virus Res 88:193-225
Menachery, Vineet D; Eisfeld, Amie J; Schäfer, Alexandra et al. (2014) Pathogenic influenza viruses and coronaviruses utilize similar and contrasting approaches to control interferon-stimulated gene responses. MBio 5:e01174-14
Schäfer, Alexandra; Baric, Ralph S; Ferris, Martin T (2014) Systems approaches to Coronavirus pathogenesis. Curr Opin Virol 6:61-9
Menachery, Vineet D; Yount Jr, Boyd L; Josset, Laurence et al. (2014) Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity. J Virol 88:4251-64
Menachery, Vineet D; Debbink, Kari; Baric, Ralph S (2014) Coronavirus non-structural protein 16: evasion, attenuation, and possible treatments. Virus Res 194:191-9
Rasmussen, Angela L; Okumura, Atsushi; Ferris, Martin T et al. (2014) Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance. Science 346:987-91
Gibbs, David L; Gralinski, Lisa; Baric, Ralph S et al. (2014) Multi-omic network signatures of disease. Front Genet 4:309
Josset, Laurence; Tchitchek, Nicolas; Gralinski, Lisa E et al. (2014) Annotation of long non-coding RNAs expressed in collaborative cross founder mice in response to respiratory virus infection reveals a new class of interferon-stimulated transcripts. RNA Biol 11:875-90
Scobey, Trevor; Yount, Boyd L; Sims, Amy C et al. (2013) Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus. Proc Natl Acad Sci U S A 110:16157-62
Chen, Yaoqing; Rajashankar, Kanagalaghatta R; Yang, Yang et al. (2013) Crystal structure of the receptor-binding domain from newly emerged Middle East respiratory syndrome coronavirus. J Virol 87:10777-83

Showing the most recent 10 out of 14 publications