title: TLR-mediated distinct IFN-γ/IL-10 pattern induces protective immunity against murine visceral leishmaniasis.
abstract: Resistance to murine visceral leishmaniasis (VL) correlates with the development of an IFN-γ predominant immune response. Beta1,4-galactose terminal glycans are potent inducers of IFN-γ. Here, we demonstrate the efficacy of a 29 kDa β1,4-galactose terminal glycoprotein (GP29) of Leishmania donovani (LD) in an in vitro macrophage model and an in vivo mouse model of VL. GP29 induced splenic macrophages to release NO and ROS in appreciable amounts that resulted in effective parasite clearance from macrophages. This was associated with the toll-like receptor (TLR)-4 mediated IL-12 induction and inhibition of TLR2-mediated IL-10 production. Two subcutaneous injections of GP29 at fortnightly intervals resulted in dominant IL-12-mediated IFN-γ production and 100% animals were protected against a subsequent challenge with virulent LD parasites. Vaccinated mice showed a reversal of T-cell anergy, significantly elevated expression of iNOS and a type-1 IgG subclass response. Moreover, vaccinated mice downregulated arginase1 and IL-10 expression but did not alter IL-4 expression. The IFN-γ/IL-10 ratio regulated the intensity of the protective immune response. Experiments with IFN-γ and IL-10 knockout mice reiterated the role IL-10 and IFN-γ play in disease progression or resolution in the murine model of VL.
authors.affiliation: Division of Infectious Disease and Immunology, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Joydeep
authors.initials: J
authors.lastname: Paul
authors.forename: Subir
authors.initials: S
authors.lastname: Karmakar
authors.forename: Tripti
authors.initials: T
authors.lastname: De
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001119:Arginase / Q000096:biosynthesis; D015536:Down-Regulation; D006023:Glycoproteins / Q000276:immunology*; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis; D007893:Leishmania donovani / Q000276:immunology / Q000472:pathogenicity; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D015800:Protozoan Proteins / Q000276:immunology; D017382:Reactive Oxygen Species; D058408:Th1-Th2 Balance; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D006023:Glycoproteins; D007074:Immunoglobulin G; D015800:Protozoan Proteins; D017382:Reactive Oxygen Species; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma; C544448:Arg1 protein, mouse; D001119:Arginase