Members of the Bcl-2 family are major regulators of apoptosis in mammalian cells, and hence
infection-induced perturbations in their expression could result into elimination of the parasites or creation of a niche favoring survival. In this investigation, we uncover a novel role of host Bcl-2 in sustaining Leishmania donovani
infection. A rapid twofold increase in Bcl-2 expression occurred in response to parasite challenge. Downregulation of post
infection Bcl-2 increase using
siRNA or functional inhibition using Bcl-2 small molecule inhibitors interfered with intracellular parasite survival confirming the necessity of elevated Bcl-2 during
infection. An increased
nitric oxide (NO) response and reduced parasitic burden was observed upon Bcl-2 inhibition, where restitution of the NO response accounted for parasite mortality. Mechanistic insights revealed a major role of elevated Th2
cytokine IL-13 in parasite-induced Bcl-2 expression via the
transcription factor STAT-3, where blocking at the level of
IL-13 receptor or downstream
kinase JAK-2 dampened Bcl-2 induction. Increase in Bcl-2 was orchestrated through
Toll like receptor (TLR)-2-MEK-ERK signaling, and changes in TLR-2 levels affected parasite uptake. In a mouse model of
visceral leishmaniasis (VL), Bcl-2 inhibitors partially restored the antimicrobial NO response by at least a twofold increase that resulted in significantly reduced parasite burden. Interestingly, monocytes derived from the peripheral blood of six out of nine human VL subjects demonstrated Bcl-2 expression at significantly higher levels, and sera from these patients showed only marginally quantifiable
nitrites. Collectively, our study for the first time reveals a pro-parasitic role of host Bcl-2 and the capacity of host-derived
IL-13 to modulate NO levels during
infection via Bcl-2. Here, we propose Bcl-2 inhibition as a possible therapeutic intervention for VL.