title: MyD88 and TLR9 dependent immune responses mediate resistance to Leishmania guyanensis infections, irrespective of Leishmania RNA virus burden.
abstract: Infections with Leishmania parasites of the Leishmania Viannia subgenus give rise to both localized cutaneous (CL), and metastatic leishmaniasis. Metastasizing disease forms including disseminated (DCL) and mutocutaneous (MCL) leishmaniasis result from parasitic dissemination and lesion formation at sites distal to infection and have increased inflammatory responses. The presence of Leishmania RNA virus (LRV) in L. guyanensis parasites contributes to the exacerbation of disease and impacts inflammatory responses via activation of TLR3 by the viral dsRNA. In this study we investigated other innate immune response adaptor protein modulators and demonstrated that both MyD88 and TLR9 played a crucial role in the development of Th1-dependent healing responses against L. guyanensis parasites regardless of their LRV status. The absence of MyD88- or TLR9-dependent signaling pathways resulted in increased Th2 associated cytokines (IL-4 and IL-13), which was correlated with low transcript levels of IL-12p40. The reliance of IL-12 was further confirmed in IL12AB-/- mice, which were completely susceptible to infection. Protection to L. guyanensis infection driven by MyD88- and TLR9-dependent immune responses arises independently to those induced due to high LRV burden within the parasites.
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Annette
authors.initials: A
authors.lastname: Ives
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Slavica
authors.initials: S
authors.lastname: Masina
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Patrik
authors.initials: P
authors.lastname: Castiglioni
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Prével
authors.affiliation: Department of Biochemistry, World Health Organization Immunology Research and Training center (WHO-IRTC), Epalinges, Switzerland.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Revaz-Breton
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Mary-Anne
authors.initials: MA
authors.lastname: Hartley
authors.affiliation: Department of Biochemistry, World Health Organization Immunology Research and Training center (WHO-IRTC), Epalinges, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Launois
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fasel
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland; Department of Biochemistry, World Health Organization Immunology Research and Training center (WHO-IRTC), Epalinges, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ronet
mesh_terms: D000818:Animals; D004198:Disease Susceptibility; D007113:Immunity, Innate; D053765:Interleukin-12 Subunit p35 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D018334:Leishmania guyanensis / Q000502:physiology / Q000821:virology*; D007897:Leishmaniasis, Mucocutaneous / Q000276:immunology / Q000473:pathology / Q000662:veterinary; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012328:RNA Viruses / Q000502:physiology*; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D018793:Interleukin-13; D053594:Myeloid Differentiation Factor 88; D051217:Toll-Like Receptor 9; D015847:Interleukin-4