Antimony-Resistant Leishmania donovani Exploits miR-466i To Deactivate Host MyD88 for Regulating IL-10/IL-12 Levels during Early Hours of Infection

Infection with antimony-resistant Leishmania donovani ((SbLD)-L-R) induces aggressive pathology in the mammalian hosts as compared with ones with antimony-sensitive L. donovani ((SbLD)-L-S) infection. (SbLD)-L-R, but not (SbLD)-L-S, interacts with TLR2/TLR6 to induce IL-10 by exploiting p50/c-Rel subunits of NF-kappa B in infected macrophages (M phi s). Most of the TLRs exploit the universal adaptor protein MyD88 to activate NF-kappa B. We now show that infection of Mfs from MyD88(-/-) mice with (SbLD)-L-R 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) M phi s. These attributes were not seen with (SbLD)-L-S in similar experiments. Further, (SbLD)-L-R infection upregulated miR-466i, which binds with 3'-untranslated region, leading to the downregulation of MyD88. Infection of MyD88(-/-) Mf or IL-12-(/-) M phi with (SbLD)-L-R induced IL-10 surge at 4 h, whereas the same in WT M phi started from 12 h. Thus, absence of IL-12 in MyD88(-/-) mice favored early binding of NF-kappa B subunits to the IL-10 promoter, resulting in IL-10 surge. Infection of MyD88(-/-) mice with (SbLD)-L-R 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 (SbLD)-L-R-infected MyD88(-/-) mice died by 60 d postinfection, whereas the WT mice continued to survive. Our results demonstrate that (SbLD)-L-R has evolved a unique strategy to evade host antileishmanial immune repertoire by manipulating host MyD88 to its advantage.