Defining the roles of TNF, lymphotoxin alpha and LIGHT in experimental visceral leishmaniasis

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Visceral leishmaniasis (VL) is an important human disease caused by the protozoan parasites Leishmania donovani and L. infantum (chagasi). Studies in experimental VL caused by L. donovani infection of mice have resulted in major insights into the causes of VL and the reasons why VL patients become severely immunocompromised. Work from our laboratory has shown that members of the TNF family of cytokines play key roles in the generation of effective immune responses during VL, but also mediate significant tissue pathology, particularly in the spleen, following L. donovani infection. In this grant, we will define the roles of several key members of the TNF family in the generation of immunity and pathology during experimental VL. We will also test if the activity of these molecules can be modulated to control disease without detrimental side effects. Results from this research have implication for the design of new vaccines and therapeutics to control VL. In addition, given the important role of TNF family members in cancers and autoimmune diseases, the work in this grant will have advance our understanding of pathogenic processes that are common to many important human diseases.