A host genetic locus that regulates susceptibility to infectious disease
Our genetic makeup affects how our immune system responds to different infectious agents. Yet, while the host immune system response to infection is clearly influenced by inherited traits, we still do not have a clear understanding of how host genetic regulation of the immune response ultimately affects disease outcome. Slam genes comprise a family of tightly linked genes that encode cell surface receptors that transduce signals through association with the cytosolic adapter protein, SLAM-associated protein (SAP). Mutations in the gene encoding SAP (Sh2d1a) results in the development of a serious immunodeficiency due to an inability to control infection, highlighting the central role that the Slam/SAP signaling pathway plays in the host response to pathogens. Slam genes are polymorphic in humans and in mice, and these polymorphisms have been linked to the development of autoimmunity. However, despite the significant role that the Slam/SAP signaling pathway plays in the host response to virus infection, there has been almost no study of the potential contribution of Slam locus polymorphisms to influence the susceptibility to host pathogens.
We are studying the contribution of naturally occurring genetic variation at the Slam locus to host susceptibility to infection. Our preliminary data indicates that one or more genes within this locus regulates the immune response to both viral and bacterial pathogens. Our working hypothesis is that genetic variation at one or more Slam genes regulates susceptibility to infection through regulation of innate-like T (i.e., gd T, NKT) cell function.
Selected Publications:
Krementsov, D.N., Case, L.K., Dienz, O., Raza, A., Fang, Q., Ather, J.L., Poynter, M.E., Boyson, J.E., Bunn, J.Y., Teuscher, C.2017. Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection. Proc Natl Acad Sci USA 114(13):3491-3496.
Huber, S.A., M. Moussawi, B. Roberts, and J.E. Boyson. 2013. Slam haplotype 2 promotes NKT but suppresses Vγ4+ T cell activation in Coxsackievirus B3 infection leading to increased liver damage but reduced myocarditis. American Journal of Pathology 182(2):401-409. PMCID: PMC3562734.
Liu, W., M. Moussawi, B. Roberts, J.E. Boyson, and S.A. Huber. 2013. Cross-Regulation of Tregulatory cell response after coxsackievirus B3 infection by NKT and γδ T cells in the mouse. American Journal of Pathology 183(2):441-449. PMCID: PMC3730787.