Abstract
Visceral leishmaniasis (VL), which is endemic as a major infectious disease in the tropical and subtropical countries, is caused by a protozoan parasite Leishmania donovani. At present, restricted treatment options and lack of vaccines intensify the problem of controlling VL. Therefore, finding a novel immunoprophylactic or therapeutic principle is a pressing need. Here, we report that arabinosylated lipoarabinomannan (Ara-LAM), a TLR2-ligand isolated from Mycobacterium smegmatis, exhibits a strong immunomodulatory property that conferred protection against L. donovani infection. Although, Ara-LAM modulates TLR2 and MAPK signaling, it is not known whether Ara-LAM involves IFN-γ signaling for effective parasite clearance. Because, it is reported that IFN-γ signaling, a principle mediator of NO generation and macrophage and Tcell activation, is hampered during leishmanial pathogenesis. Ara-LAM increases IFN-γ receptor expression and potentiates IFN-γ receptor signaling through JAK-STAT pathway. Moreover, Ara-LAM reciprocally modulates IRF4 and IRF8 expression and reinstates anti-leishmanial Th1 response that eventuates in significantly reduced parasite load in spleen and liver of L. donovani-infected BALB/c mice. IFN-γRα silencing resulted in the suppression of these host-protective mechanisms affected by Ara-LAM. Thus, Ara-LAM-mediated restoration of IFN-γ responsiveness is a novel immuno-modulatory principle for protection against L. donovani susceptible host.
Highlights
Visceral leishmaniasis (VL), caused by a protozoan parasite Leishmania donovani, is one of the most widespread infectious diseases affecting many countries [1]
We examined whether arabinosylated lipoarabinomannan (Ara-LAM) pre-treatment would enhance IFN-γ receptor α-chain (IFN-γRα) expression in BALB/c-derived thioglycolate-elicited L. donovani-infected macrophages
We observed that the IFN-γRα expression started decreasing 3 hours after the infection (Fig. 1A) and Ara-LAM prevented the reduction in IFN-γRα expression in L. donovani-infected macrophages (Fig. 1A, 1B, 1C; p< 0.05) possibly by enhancing NF-κB binding to IFN-γRα promoter (Fig. 1D)
Summary
Visceral leishmaniasis (VL), caused by a protozoan parasite Leishmania donovani, is one of the most widespread infectious diseases affecting many countries [1]. It is re-emerging as a major disease due to lack of effective chemotherapy and vaccine [2] and due to co-infection with HIV [3]. The HIV-Leishmania co-infection is virtually untreatable [4]. As Leishmania expressed lipophosphoglycan (LPG) interacts with the macrophage expressed TLR2 [6, 7], which subsequently regulates the expression and function of the leishmanial DNA recognizing TLR9 [8, 9], TLR2 is targeted for developing an anti-leishmanial immunotherapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
