The clinical outcome of many infectious diseases is contributed to by a mix of genetic factors from both the host and the parasite. Cutaneous leishmaniasis, caused by the parasite L. major is an exampleof a disease where the host genetic factors play a major role in the severity of the disease. Clinical severity is determined by the type of T helper cell response mounted to the parasite, a Th1 response is associated with a small, rapidly healing ulcer whereas a Th2 response associates with the severe forms of the disease. In mice a similar picture is seen with the added observation that the Th responses are strongly under the control of the genetics of the different mouse strains. An understanding of the underlying genetic influences on outcome to L. major may result in an understanding of the genes controlling the T helper cell subsets in humans. Three loci have been identified which mediate resistance and susceptibility towards L. major in mice. Congenic animals for these loci either have been bred or are in the process of being bred. These mice will be used to fine map the location of the genes underpinning these loci. Positional cloning strategies will be used to identify the genes themselves. These include the use of BAC transgenic complementation, allelic substitute is ES cells and classic candidate gene identification with subsequent transgenic validation. The biology of the control of susceptibility to L. major will be studied using the congenic animals. The T cell response will be studied. The ability of macrophages and dendritic cells to support parasite growth will be investigated. Initial results indicate that the loci identified as being important in resistance to L. major also play a role in other infectious diseases, notably S. mansoni and S. typhimurium.. These observations will be pursued further. Many other diseases are thought to be due to an underlying problem in teh Th1/Th2 response. These include many autoimmune diseases, transplantation rejection, and many infectious diseases. The congenic animals will be used to study the role of the leishmani modifier loci in some of these conditions. The ultimate anticipated outcome is a better comprehension of the factors that go in to the regulation of the Th response to L. major with possible spin-off benefits in other diseases.
