Research Projects

Visceral leishmaniasis (VL) is a health concern in tropical countries including India. In endemic regions, humans are affected due to infection by protozoan parasite Leishmania donovani (LD). Despite substantial improvement in VL scenario in India, there are concerns remain due to recent reports of high fatality in infected patients, spreading of the vector sandfly in previously unreported states and the notorious tendency of the parasite in gaining drug resistance. Any vaccine against VL is still elusive. So, there is a continuous need to identify the novel drug targets for treating VL. We observed that LD infection activates the transcription factor HIF-2 by increasing its regulatory subunit HIF-2α in host macrophages (primary and cell lines). Macrophages are the host cells LD utilizes during its mammalian cycle of survival. Intriguingly, knocking down of HIF-2α critically affected survival of intracellular LD. Moreover, we detected the exosomes derived from LD also regulates HIF-2α to activate HIF-2 in macrophages. These observations led us to hypothesize that LD exploits activation of HIF-2 in the host macrophages for its survival advantage. Thus, the HIF-2α could be a potential drug target for combating LD. The recent emergence of HIF-2α inhibitors as cancer drugs could be useful as a repurpose drug for VL. We shall test this hypothesis by understanding the mechanism of HIF-2α regulation during LD infection and exosome exposure. To identify the HIF-2 activated target(s) by which LD maintains its survival in challenging environment of macrophages. Exploring the efficacy of HIF-2α inhibitors on LD (drug resistance and drug sensitive) survival and proliferation in macrophages and in LD infected Balb/c mice.