Mallick, S. and Dutta, A. and Chaudhuri, , A. and Mukherjee, D. and Dey, S. and Halder, S. and Ghosh, J. and Mukherjee, D. and Sultana, S.S. and Biswas, G. and Lai, T.K. and Patra, P. and Sarkar , I. and Chakraborty, S. and Saha, B. and Krishnedu, A. and Pal , C. (2016) Successful therapy of murine visceral leishmaniasis with astrakurkurone, a triterpene isolated from mushroom Astraeus hygrometricus, involves the induction of protective cell mediated immunity and TLR9. Antimicrob Agents and Chemother, 60 (5). pp. 2696-2708.

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Abstract

In our preceding report, we have shown that astrakurkurone, a triterpene, isolated from Indian mushroom Astraeus hygrometricus (Pers.) Morgan induced reactive oxygen species leading to apoptosis in Leishmania donovani promastigotes and also effective in inhibiting intracellular amastigotes at the IC50 concentration of 2.5 μg/ml. The aim of the present study is to characterize the associated immunomodulatory potentials and cellular activation provided by astrakurkurone leading to effective anti-leishmanial activity, in vitro and in vivo. Astrakurkurone-mediated antileishmanial activity was evaluated by real time PCR and flowcytometry. The involvement of TLR9 was studied by in vitro assay in presence of TLR9 agonist and antagonist and in silico modelling of three-dimensional structure of ectodomain of TLR9 and its interaction with astrakurkurone. Astrakurkurone caused a significant increase in TLR9 expression of L. donovani-infected macrophages along with the activation of proinflammatory responses. The involvement of TLR9 in astrakurkurone-mediated amastigote killing has been evidenced from the fact that TLR9 agonist (CpG ODN) in combination with astrakurkurone enhanced the amastigote killing whilst TLR9 antagonist (bafilomycin A1) alone or in combination with astrakurkurone curbed the amastigote killing which could be further justified by in silico evidences of docking complex between mouse TLR9-astrakurkurone. Astrakurkurone was found to reduce the parasite burden in vivo by inducing protective cytokines, IFN-γ and IL-17. Moreover, astrakurkurone was found non-toxic towards PBMC of immunocompromised VL patients. Astrakurkurone, a non-toxic antileishmanial lead enhances the immune efficiency of host cells leading to parasite clearance in vitro and in vivo.

Item Type:	Article
Subjects:	Infection and Immunity
Depositing User:	Mr. Rameshwar Nema
Date Deposited:	14 Dec 2016 09:22
Last Modified:	14 Dec 2016 09:22
URI:	http://nccs.sciencecentral.in/id/eprint/323

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