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 (Sb(R)LD) induces aggressive pathology in the mammalian hosts as compared with ones with antimony-sensitive L. donovani (Sb(S)LD) infection. Sb(R)LD, but not Sb(S)LD, 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 Sb(R)LD 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 Sb(S)LD in similar experiments. Further, Sb(R)LD 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 Sb(R)LD 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 Sb(R)LD 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 Sb(R)LD-infected MyD88(-/-) mice died by 60 d postinfection, whereas the WT mice continued to survive. Our results demonstrate that Sb(R)LD has evolved a unique strategy to evade host antileishmanial immune repertoire by manipulating host MyD88 to its advantage.
Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology, Kolkata 700032, India;
Budhaditya
B
Mukherjee
Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology, Kolkata 700032, India;
Joydeep
J
Paul
Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology, Kolkata 700032, India;
Sandip
S
Mukherjee
Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology, Kolkata 700032, India;
Rupkatha
R
Mukhopadhyay
Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology, Kolkata 700032, India;
Shantanabha
S
Das
Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology, Kolkata 700032, India;
Kshudiram
K
Naskar
Institute of Medical Sciences, Benaras Hindu University, Varanasi 221005, India;
Shyam
S
Sundar
Institute of Tropical Medicine, Antwerp 2000, Belgium; University of Antwerp, Antwerp 2000, Belgium; and.
Jean-Claude
JC
Dujardin
National Centre for Cell Science, Pune 411007, India.
Bhaskar
B
Saha
Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology, Kolkata 700032, India; sroy@iicb.res.in.
Syamal
S
Roy
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000965:Antimony / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D004351:Drug Resistance / Q000235:genetics; D016753:Interleukin-10 / Q000378:metabolism*; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000378:metabolism*; D007893:Leishmania donovani / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000276:immunology
D020413:3' Untranslated Regions; C556062:IL10 protein, mouse; C508859:Il12a protein, mouse; D053765:Interleukin-12 Subunit p35; D035683:MicroRNAs; C576133:Mirn466 microRNA, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D034741:RNA, Small Interfering; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D016753:Interleukin-10; D000965:Antimony