Leishmania tropica: immunopathology and genetic control

Leishmaniasis is a neglected tropical disease caused by protozoan parasites of the genus Leishmania and transmitted by female sand flies. The outcome of Leishmania infection depends both on host and pathogen factors. There are three major clinical forms of leishmaniasis: cutaneous, mucocutaneous and visceral. Similarly as L. major, L. tropica very often causes cutaneous leishmaniasis in humans, but in rare occasions can also visceralize and cause systemic disease. Leishmaniasis caused by L. tropica has become a major public health problem in different endemic foci due to recent outbreaks in several urban areas and spread to new regions. The complications of the disease and lack of safe, effective and affordable drug and vaccine against L. tropica infection require considerable attention to studies of the host-L. tropica interaction. Until recently, the research of leishmaniasis caused by L. tropica was limited due to lack of suitable inbred model and difficulties in inducing infection in animals. This thesis summarizes the results of my PhD project devoted to development of a suitable mouse model of the infection caused by L. tropica, study of mechanisms of the disease, and also mapping controlling genes/loci. We analyzed susceptibility to L. tropica infection using recombinant congenic (RC) CcS/Dem strains. We identified CcS-16 and CcS-9 as highly susceptible strains to L. tropica infection. We showed that CcS-9 strain not only has large lesions but also developed visceral pathology after infection with L. tropica. Based on the results of massive histological analysis and gene expression we showed that probably the intensive inflammation in visceral organs and skin is the main reason for splenomegaly, hepatomegaly and large skin pathology in CcS-9 infected mice. In F2 hybrids between BALB/c and CcS-16 we detected and mapped eight gene-loci, Ltr1-8 (Leishmania tropica response 1-8) that control various manifestations of disease: skin lesions, splenomegaly, hepatomegaly, parasite numbers in spleen, liver, and inguinal lymph nodes, and serum level of CCL3, CCL5, and CCL7 after L. tropica infection. These results represent the first mapping of L. tropica susceptibility loci in any species. In our human study we identified the CD8+ T cells as the main producer of IFN-γ which might be the responsible cells for maintenance of protective immune response against human leishmaniasis. The availability of an informative animal model enabled us to study mechanisms of the disease and map gene/loci participating in the control of resistance to L. tropica. This knowledge may also provide hints for the development of novel strategies of the disease control. Further deep characterization of L. tropica infection in CcS-9 and CcS-16 strains may help to understand the detailed mechanisms of the disease and would open new perspectives of the research, treatment and vaccine development against leishmaniasis caused by this parasite. The present data about CD8+ T cells might be used as a basis for future investigations of memory T cells in human leishmaniasis and might have an implication in the development of an effective vaccine.