Systems immunogenetics of biodefense and emerging pathogens in the collaborative cross – Influenza (IAV) response study
The central objective of the research consortium 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. 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. Therefore, the 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, the consortium 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.
The central objective in project 2 (directed by Schughart and Heise) is to study the host response to respiratory infections (IAV) in mouse model systems and human patients. Respiratory viruses, such as IAV, SARS and RSV cause high levels of morbidity and mortality in human populations. Host immune responses can play either protective or a pathologic role during infection. Therefore, understanding of the regulatory networks and signaling pathways that determine the magnitude and quality of an individual’s antiviral immune response has important implications for human health, since these genes/pathways could be therapeutically targeted to control viral replication, to treat aberrant immune responses, or they may represent targets for enhancing the safety and efficacy of vaccines against a wide range of viral pathogens. Dr. Schughart and clinical co-investigators at Baptist’s Memorial Hospital Memphis, and LeBonheur Childrens Hospital Memphis, and Duke University Hospital Durham and Magdeburg University Hopsital) will collect samples from patients infected by respiratory viruses (with an emphasis on influenza virus) and perform transcriptome and genotyping studies to identify genes that are differentially expressed (DEG) in infected versus healthy controls and in patients with severe diseases versus patients with moderate disease. The identified DEG will then be functionally investigated in details in our mouse model system.
- Infection Genetics- Prof. Dr. Klaus Schughart
Prof. Dr. Ralph Baric (UNC), Prof. Dr. Mark Heise (UNC)
NIAID - National Institutes of Allergy and Infectious Disease