Leishmania donovani-Induced Increase in Macrophage Bcl-2 Favors Parasite Survival.
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 sustainingLeishmania donovaniinfection. 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 Th2cytokine IL-13 in parasite-induced Bcl-2 expressionviathe 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 infectionviaBcl-2. Here, we propose Bcl-2 inhibition as a possible therapeutic intervention for VL.
Cell Death and Differentiation Research Laboratory, National Institute of Immunology , New Delhi , India.
Rajeev Kumar
RK
Pandey
Department of Human Genetics, Guru Nanak Dev University , Amritsar , India.
Sanjana
S
Mehrotra
Department of Medicine, Institute of Medical Sciences, Infectious Disease Research Laboratory, Banaras Hindu University , Varanasi , India.
Smriti
S
Sharma
Central Animal Facility, Indian Institute of Science , Bangalore , India.
Ramachandra Subbaraya
RS
Gudde
Department of Medicine, Institute of Medical Sciences, Infectious Disease Research Laboratory, Banaras Hindu University , Varanasi , India.
Shyam
S
Sundar
Cell Death and Differentiation Research Laboratory, National Institute of Immunology , New Delhi , India.
Chandrima
C
Shaha
ABT-199; Bcl-2; IL-13; Leishmania donovani; macrophage; nitric oxide