Regulatory actions of Toll-like receptor 2 (TLR2) and TLR4 in Leishmania donovani infection in the liver.

TitleRegulatory actions of Toll-like receptor 2 (TLR2) and TLR4 in Leishmania donovani infection in the liver.
Publication TypeJournal Article
Year of Publication2013
AuthorsMurray HW, Zhang Y, Zhang Y, Raman VS, Reed SG, Ma X
JournalInfect Immun
Date Published2013 Jul
KeywordsAnimals, Antiprotozoal Agents, Disease Models, Animal, Female, Gene Expression Regulation, Interferon-gamma, Interleukin-10, Leishmania donovani, Leishmaniasis, Visceral, Lipopeptides, Liver, Macrophages, Mice, Mice, Inbred C57BL, Nitric Oxide Synthase Type II, RNA, Messenger, Signal Transduction, Toll-Like Receptor 2, Toll-Like Receptor 4

In livers of susceptible but self-curing C57BL/6 mice, intracellular Leishmania donovani infection enhanced Toll-like receptor 4 (TLR4) and TLR2 gene expression. In the liver, infected TLR4(-/-) mice showed reduced gamma interferon (IFN-γ), tumor necrosis factor (TNF), and inducible nitric oxide synthase (iNOS) mRNA expression, higher-level and slowly resolving infection, delayed granuloma formation, and little response to low-dose chemotherapy; in serum, the ratio of IFN-γ to interleukin 10 (IL-10) activity was decreased by 50%. In contrast, in TLR2(-/-) mice, control of liver infection, parasite killing, and granuloma assembly were accelerated and chemotherapy's efficacy enhanced. In livers of infected TLR2(-/-) mice, mRNA expression was not increased for inflammatory cytokines or iNOS or decreased for IL-10; however, the serum IFN-γ/IL-10 ratio was increased 6.5-fold and minimal responses to IL-10 receptor blockade suggested downregulated IL-10. In established infection in wild-type mice, blockading TLR2 induced parasite killing and triggering TLR4 strengthened resistance and promoted chemotherapy's effect. Thus, in experimental L. donovani infection in the liver, TLR4 signaling upregulates and TLR2 signaling downregulates macrophage antileishmanial activity, making both receptors potential therapeutic targets in visceral leishmaniasis for engagement (TLR4) or blockade (TLR2).

Alternate JournalInfect Immun
PubMed ID23589575
PubMed Central IDPMC3697629
Grant ListR01 AI083219 / AI / NIAID NIH HHS / United States
R01 AI025038 / AI / NIAID NIH HHS / United States
5R01AI083219 / AI / NIAID NIH HHS / United States
1R56AI095512 / AI / NIAID NIH HHS / United States
R56 AI095512 / AI / NIAID NIH HHS / United States
R01AI025038 / AI / NIAID NIH HHS / United States

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