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

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Title Antimony-Resistant Leishmania donovani Exploits miR-466i to Deactivate Host MyD88 for Regulating IL-10/IL-12 Levels during Early Hours of Infection
 
Creator Mukherjee, Budhaditya
Pau, Joydeep l
Mukherjee, Sandip
Mukhopadhyay, Rupkatha
Das, Shantanabha
Naskar, Kshudiram
Sundar, Shyam
Dujardin, Jean-Claude
Saha, Bhaskar
Roy, Syamal
 
Subject Infectious Diseases and Immunology
 
Description 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-kB in infected macrophages (Mfs). Most of the TLRs exploit the universal adaptor protein MyD88 to activate NF-kB. We now show that infection of Mfs from MyD882/2 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) Mfs. Ī¤hese attributes were not seen with SbSLD in similar experiments. Further, SbRLD infection upregulated miR-466i, which binds with 39-untranslated region, leading to the downregulation of MyD88. Infection of MyD882/2 Mf or IL-122/2 Mf with SbRLD induced IL-10 surge at 4 h, whereas the same in WT Mf started from 12 h. Thus, absence of IL-12 in MyD882/2 mice favored early binding of NF-kB subunits to the IL-10 promoter, resulting in IL-10 surge. Infection of MyD882/2 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 MyD882/2 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.
 
Publisher American Association of Immunologists
 
Date 2015
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2360/1/JOURNAL_OF_IMMUNOLOGY__V._195_(__6__)_2731%2D2742_;2015.pdf
Mukherjee, Budhaditya and Pau, Joydeep l and Mukherjee, Sandip and Mukhopadhyay, Rupkatha and Das, Shantanabha and Naskar, Kshudiram and Sundar, Shyam and Dujardin, Jean-Claude and Saha, Bhaskar and Roy, Syamal (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. ISSN 0022-1767
 
Relation http://dx.doi.org/doi/10.4049/jimmunol.1402585
http://www.eprints.iicb.res.in/2360/