September 19, 2017
The National Institute of Allergy and Infectious Diseases has renewed a 5-year grant managed by co-principal investigators Ralph S. Baric, PhD, professor of epidemiology in the UNC Gillings School of Global Public Health, and Mark Heise, PhD, professor of genetics in the UNC School of Medicine.
The grant, titled “Systems Immunogenetics of Biodefense and Emerging Pathogens in the Collaborative Cross,” will run from Sept. 1, 2017, to Aug. 30, 2022, with a funding amount of approximately $11.5 million.
The overarching premise of the grant is the development of new mouse models that replicate the genetic diversity found in humans. These “outbred” models will allow researchers to better understand how natural genetic variation regulates immune and disease outcomes following infection with highly pathogenic emerging viruses.
“This strategy is key for understanding the genetic regulation of the immune response,” the co-principal investigators explained. “The knowledge we can gain is essential for improving precision medicine, disease prediction, and the diagnosis and treatment of infectious and immune disorders in humans. Furthermore, new model systems that more accurately reproduce human disease will be critical for developing the next generation of antiviral drugs and vaccines.”
By working with the UNC Collaborative Cross panel, a mouse genetic reference population specifically designed to model genetically complex populations such as humans, the researchers hope to identify and map the specific genes that interact to regulate virus immunity. Then, they will work to elucidate the molecular mechanisms by which these genes control protective or pathogenic host immune responses following infection.
In addition to the development and dissemination of a revolutionary genetic mapping platform, another primary goal of the grant is to validate precision medicine models that will predict and test gene function with disease outcomes in outbred mouse populations. Eventually, these models could evaluate the role of natural variation in human genes that fight disease.
“We believe that many susceptibility gene sets that regulate protective or pathogenic immune responses in the Collaborative Cross mice can be integrated with existing human datasets,” Baric said. “This integration could help us more accurately identify causal associations between specific human genetic traits and infection outcomes, ultimately leading to new strategies for intervention, treatment and control.”
Emerging pathogens that Baric and colleagues will study include the highly pathogenic influenza A virus, SARS coronavirus and West Nile virus, in addition to Middle East respiratory syndrome coronavirus, Ebola virus and Zika virus.
In particular, Baric’s group will focus on identifying susceptibility alleles that regulate SARS coronavirus disease mechanisms and immunity; this work will build on previous findings noted by Lisa Gralinski, PhD, a member of the group and a research assistant professor in the Gillings School’s Department of Epidemiology.
“Using the Collaborative Cross will allow us to identify novel genes, as well as entire pathways, that regulate emerging coronavirus pathogenesis,” Gralinski said. “The natural genetic variation of the Cross population will enable us to probe the interplay between host signaling pathways so we can begin to dissect the complex interactions that lead to serious diseases like acute respiratory distress syndrome.”
Baric’s group also will work closely with Vineet Menachery, PhD, a former postdoctoral scholar of epidemiology in the Gillings School who is now an assistant professor at the University of Texas Medical Branch. Other members of the research team include Fernando Pardo-Manuel de Villena, PhD, professor and interim chair, and Marty Ferris, PhD, research assistant professor, both in the Department of Genetics in the UNC School of Medicine; Klaus Schughart, PhD, from the University of Tennessee; Michael Gale, Jr., PhD, from the University of Washington; Jenny Lund, PhD, from the Fred Hutchinson Cancer Research Center; and Shannon McWeeney, PhD, from Oregon Health Sciences University.