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

Abstract

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.

• Authors: Budhaditya Mukherjee, Joydeep Paul, Sandip Mukherjee, Rupkatha Mukhopadhyay, Shantanabha Das, Kshudiram Naskar, Shyam Sundar, Jean-Claude Dujardin, Bhaskar Saha, Syamal Roy
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 195 Issue 6 Pg. 2731-42 (Sep 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 26283478 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• 3' Untranslated Regions
• IL10 protein, mouse
• Il12a protein, mouse
• Interleukin-12 Subunit p35
• MicroRNAs
• Mirn466 microRNA, mouse
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• NF-kappa B
• RNA, Small Interfering
• Tlr2 protein, mouse
• Tlr6 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 6
• Interleukin-10
• Antimony

Topics

• 3' Untranslated Regions (genetics)
• Animals
• Antimony (pharmacology)
• Cells, Cultured
• Cricetinae
• Drug Resistance (genetics)
• Interleukin-10 (metabolism)
• Interleukin-12 Subunit p35 (genetics, metabolism)
• Leishmania donovani (drug effects, genetics, immunology)
• Leishmaniasis, Visceral (immunology, pathology)
• Macrophages (immunology, parasitology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (genetics)
• Myeloid Differentiation Factor 88 (genetics, immunology)
• NF-kappa B (immunology)
• RNA Interference
• RNA, Small Interfering
• Toll-Like Receptor 2 (immunology)
• Toll-Like Receptor 6 (immunology)