Genetic factors influencing susceptibility to intracellular infections

Sammanfattning: Genetics of susceptibility to infection is a complex trait in which many factors from the host, the parasite and the environment, interact to produce different clinical manifestations of disease. This thesis explores the relationship between the first infectious susceptibility gene ever cloned, SLC11A1 and the occurrence of intracellular infections (leprosy, leishmaniasis and HIV infection) in several populations of humans. It also demonstrates the use of an animal model as the basis for mapping new susceptibility loci for tuberculosis. Through this work it was found that part of the effect of susceptibility to leprosy per se in Vietnamese families is under the control of SLC11A1 In addition, this gene appears to influence the immune response to the Mitsuda reaction (which indicates acquired immunity to Mycobacterium leprae) providing proof of principle that qualitative measures of immune reactivity can be mapped to particular loci in family studies. In contrast, susceptibility to leishmaniasis does not seem to be under the control of SLC11A1. Additionally, this thesis shows that allelic variants of SLC11A1 are associated with altered risk of HIV infection. This work also includes further analysis on previously detected susceptibility loci in the A/Sn x I/St mouse model of tuberculosis. The results of the study allow a more precise location of candidate susceptibility regions and provide evidence that gene x gene interactions can be studied in animal models of disease. We found evidence of multigenic control to severity of disease in mice, since QTLs on chromosomes 9 (tbs2), 3 (tbs1) and 17, interacted to modify the phenotype. An additional interacting locus on chromosome X (lmr3) provided support for explaining previously observed sex effects on the phenotype. Phagocytes derived from I/Sn animals appear to have a defect in their phagocytic activity compared to cells obtained from A/Sn mice since Mycobacterium tuberculosis infected cells are more abundant and contain more bacteria in I/St mice. The defect seems to be specific of alveolar phagocytes and seems to occur early during in vitro infection experiments.