title: MyD88 signaling is required for efficient innate and adaptive immune responses to Paracoccidioides brasiliensis infection.
abstract: The mechanisms that govern the initial interaction between Paracoccidioides brasiliensis, a primary dimorphic fungal pathogen, and cells of the innate immunity need to be clarified. Our previous studies showed that Toll-like receptor 2 (TLR2) and TLR4 regulate the initial interaction of fungal cells with macrophages and the pattern of adaptive immunity that further develops. The aim of the present investigation was to assess the role of MyD88, an adaptor molecule used by TLRs to activate genes of the inflammatory response in pulmonary paracoccidioidomycosis. Studies were performed with normal and MyD88(-/-) C57BL/6 mice intratracheally infected with P. brasiliensis yeast cells. MyD88(-/-) macrophages displayed impaired interaction with fungal yeast cells and produced low levels of IL-12, MCP-1, and nitric oxide, thus allowing increased fungal growth. Compared with wild-type (WT) mice, MyD88(-/-) mice developed a more severe infection of the lungs and had marked dissemination of fungal cells to the liver and spleen. MyD88(-/-) mice presented low levels of Th1, Th2, and Th17 cytokines, suppressed lymphoproliferation, and impaired influx of inflammatory cells to the lungs, and this group of cells comprised lower numbers of neutrophils, activated macrophages, and T cells. Nonorganized, coalescent granulomas, which contained high numbers of fungal cells, characterized the severe lesions of MyD88(-/-) mice; the lesions replaced extensive areas of several organs. Therefore, MyD88(-/-) mice were unable to control fungal growth and showed a significantly decreased survival time. In conclusion, our findings demonstrate that MyD88 signaling is important in the activation of fungicidal mechanisms and the induction of protective innate and adaptive immune responses against P. brasiliensis.
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas da Universidade de São Paulo, Av. Prof. Lineu Prestes 1730, CEP 05508-900, São Paulo, SP, Brazil.
authors.forename: Flávio V
authors.initials: FV
authors.lastname: Loures
authors.forename: Adriana
authors.initials: A
authors.lastname: Pina
authors.forename: Maíra
authors.initials: M
authors.lastname: Felonato
authors.forename: Claudia
authors.initials: C
authors.lastname: Feriotti
authors.forename: Eliseu F
authors.initials: EF
authors.lastname: de Araújo
authors.forename: Vera L G
authors.initials: VL
authors.lastname: Calich
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D007113:Immunity, Innate / Q000276:immunology; D020382:Interleukin-18 / Q000096:biosynthesis; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D010228:Paracoccidioides / Q000276:immunology*; D010229:Paracoccidioidomycosis / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: D020382:Interleukin-18; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors