Mukherjee, A. and Paul, J. and Mukherjee , S. and Mukhopadhyay, R. and Das , S. and Naskar, K. and Sundar, S. and Dujardin, J.C. and Saha , B. and Roy, S. (2015) Antimony-Resistant Leishmania donovani Exploits miR-466i To Deactivate Host MyD88 for Regulating IL-10/IL-12 Levels during Early Hours of Infection. The Journal of Immunology , 195 (6). pp. 2731-2742.

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Abstract

Infection with antimony-resistant Leishmania donovani (SbRLD) induces aggressive pathology in the mammalian hosts as compared with ones with antimony-sensitive L. donovani (SbSLD) infection. SbRLD, but not SbSLD, interacts with TLR2/TLR6 to induce IL-10 by exploiting p50/c-Rel subunits of NF-κB in infected macrophages (Mϕs). Most of the TLRs exploit the universal adaptor protein MyD88 to activate NF-κB. We now show that infection of Mϕs from MyD88−/− mice with SbRLD gave rise to significantly higher intracellular parasite number coupled with elevated IL-10/IL-12 ratio in the culture supernatant as compared with infection in wild type (WT) Mϕs. Τhese attributes were not seen with SbSLD in similar experiments. Further, SbRLD infection upregulated miR-466i, which binds with 3′-untranslated region, leading to the downregulation of MyD88. Infection of MyD88−/− Mϕ or IL-12−/− Mϕ with SbRLD induced IL-10 surge at 4 h, whereas the same in WT Mϕ started from 12 h. Thus, absence of IL-12 in MyD88−/− mice favored early binding of NF-κB subunits to the IL-10 promoter, resulting in IL-10 surge. Infection of MyD88−/− mice with SbRLD showed significantly higher organ parasites coupled with ill-defined and immature hepatic granulomas, whereas in WT mice there were less organ parasites and the granulomas were well defined. From the survival kinetics it was observed that SbRLD-infected MyD88−/− mice died by 60 d postinfection, whereas the WT mice continued to survive. Our results demonstrate that SbRLD has evolved a unique strategy to evade host antileishmanial immune repertoire by manipulating host MyD88 to its advantage.

Item Type:	Article
Subjects:	Infection and Immunity
Depositing User:	Mr. Rameshwar Nema
Date Deposited:	15 Dec 2016 02:17
Last Modified:	15 Dec 2016 02:17
URI:	http://nccs.sciencecentral.in/id/eprint/326

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