Research Lab of Cory Teuscher, Ph.D.
Areas of interest: genetics, immunobiology, microbial pathogenesis, immunogenetics, infectious/autoimmune diseases.
The major focus of the research effort in my laboratory is the identification and characterization of non-classical immune response genes controlling susceptibility and resistance to immunopathologically mediated diseases. These include murine models of both infectious and autoimmune disease. The overall strategy is to use forward genetics to identify genes of interest. With respect to infectious diseases, we have mapped loci that control the quantitative variation in a number of the component phenotypes seen in murine Lyme disease. Similarly, we have identified quantitative trait loci (QTL) which govern phenotypic variation in a number of traits associated with Theiler’s murine encephalomyelitis induced demyelination, an infectious disease model for multiple sclerosis (MS). The autoimmune disease models that we study are experimental allergic encephalomyelitis (EAE), experimental allergic orchitis (EAO), and day three thymectomy induced autoimmune ovarian dysgenesis (AOD). For each of these models we have identified a large number of QTL many of which co-localize with genetic regions implicated in other autoimmune and infectious diseases. This lead us to hypothesize that there may be both common and disease-specific loci that regulate susceptibility to immunopathologically mediated phenotypes, i.e., share immunopathology disease gene hypothesis. This was proven true for Bphs, an autoimmune disease susceptibility gene implicated in both EAE and EAO and susceptibility to B. pertussis toxin, when all three genes were identified as histamine H1 receptor. Similarly, we showed that a 2538 G-->A missense mutation in tyrosine-2 (Tyk2) controlling opposing differential susceptibility to Toxoplasma gondii and autoimmune arthritis is also a susceptibility gene in EAE whose effect is environmentally sensitive. Importantly, TYK2 has been identified as a susceptibility gene in GWAS studies for multiple sclerosis and systemic lupus erythematosis making Tyk2/TYK2 a shared immunopathology gene in both human autoimmune disease and their animals models. Studies are currently underway to delineate the mechanism whereby Hrh1 and Tyk2/TYK2 alleles function in disease pathogenesis.
|Laure Case||Postdoctoral Associate||(802) 656-9024|
|Kristiaan Finstad||Research Technician||(802) 656-8391|
|Dimitry Krementsov||Postdoctoral Fellow||(802) 656-9024|
|Erin Osmanski||Research Lab Assistant||(802) 656-8391|
|Naresha Saligrama||Predoctoral Student||(802) 656-9355|
|Emma Wall||Postdoctoral Associate||(802) 656-9024|
Programs & Projects
A co-evolutionary genetic link between susceptibility to infectious and autoimmune disease has long been suspected. In the molecular arms race between pathogens and host defense genes, polymorphism in genes controlling antigen-specific molecular interactions are considered the quintessential examples of infectious disease gene alleles that contribute to autoimmune disease susceptibility. However, it has been estimated that approximately half of the host genetic variability contributing to infectious disease resistance is a function of genes encoding for non-antigen specific molecules. Thus, the identification of polymorphic, non-antigen dependent molecules controlling susceptibility to infectious agents, or their products, and autoimmune disease would provide considerable insight into the nature of such genes. With the advent of genome scanning technology and high resolution congenic mapping, a large number of infectious and autoimmune disease susceptibility loci have been mapped. Early on it became evident that several of these loci resided on the same chromosomes and colocalized within the same genetic intervals. We hypothesized that this phenomenon represented either single, shared disease susceptibility genes or members of gene complexes involved in multiple immunopathologically mediated phenotypes. This hypothesis has recently been validated when we identified Bphs, the locus controlling susceptibility to Bordetella pertussis induced hypersensitivity to histamine and autoimmune disease in mice, as the histamine H1 receptor. Mechanistically, Bphs/Hrh1 controls both the induction and effector phases of the disease process. Similar positional-candidate gene cloning approaches are underway to identify genes underlying previously mapped infectious and autoimmune disease QTL in the mouse.
Last modified March 11 2013 12:02 PM