title: Leishmania expressed lipophosphoglycan interacts with Toll-like receptor (TLR)-2 to decrease TLR-9 expression and reduce anti-leishmanial responses.
abstract: Two different Toll-like receptors (TLRs) have been shown to play a role in host responses to Leishmania infection. TLR-2 is involved in parasite survival in macrophages upon activation by lipophosphoglycan (LPG), a virulence factor expressed by Leishmania. In contrast, activation of TLR-9 has been shown to promote a host-protective response. However, whether there is a relationship between the interaction of LPG and TLR-2, on one hand, with the effect of TLR-9, on the other hand, remains unknown. In this study, we report that in-vitro infection of macrophages with a L. major parasite with high expression levels of LPG results in decreased TLR-9 expression compared to infection with a L. major parasite with lower expression levels of LPG. Addition of anti-LPG as well as anti-TLR-2 antibodies prevents this reduction of TLR-9 expression. Also, the addition of purified LPG to macrophages results in a decrease of TLR-9 expression, which is shown to be mediated by transforming growth factor (TGF)-β and interleukin (IL)-10. Finally, in-vitro treatment of macrophages with anti-LPG and/or anti-TLR-2 antibodies before infection reduces the number of amastigotes in macrophages and co-treatment of mice with anti-TLR-2 antibodies and cytosine-phosphate-guanosine (CpG) reduces footpad swelling and parasite load in the draining lymph nodes, accompanied by an interferon (IFN)-γ-predominant T cell response. Thus, for the first time, we show how interactions between LPG and TLR-2 reduce anti-leishmanial responses via cytokine-mediated decrease of TLR-9 expression.
authors.affiliation: National Centre for Cell Science, Pune, India.
authors.forename: S
authors.initials: S
authors.lastname: Srivastava
authors.forename: S P
authors.initials: SP
authors.lastname: Pandey
authors.forename: M K
authors.initials: MK
authors.lastname: Jha
authors.forename: H S
authors.initials: HS
authors.lastname: Chandel
authors.forename: B
authors.initials: B
authors.lastname: Saha
mesh_terms: D000818:Animals; D018899:CpG Islands / Q000276:immunology; D015870:Gene Expression; D006028:Glycosphingolipids / Q000235:genetics / Q000276:immunology*; D006790:Host-Parasite Interactions / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D018320:Leishmania major / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology / Q000469:parasitology / Q000628:therapy; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000276:immunology
chemical_list: D006028:Glycosphingolipids; C556062:IL10 protein, mouse; C493486:Tlr2 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D016212:Transforming Growth Factor beta; C008290:lipophosphonoglycan; D016753:Interleukin-10; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse