title: 5-Lipoxygenase deficiency impairs innate and adaptive immune responses during fungal infection.
abstract: 5-Lipoxygenase-derived products have been implicated in both the inhibition and promotion of chronic infection. Here, we sought to investigate the roles of endogenous 5-lipoxygenase products and exogenous leukotrienes during Histoplasma capsulatum infection in vivo and in vitro. 5-LO deficiency led to increased lung CFU, decreased nitric oxide production and a deficient primary immune response during active fungal infection. Moreover, H. capsulatum-infected 5-LO(-/-) mice showed an intense influx of neutrophils and an impaired ability to generate and recruit effector T cells to the lung. The fungal susceptibility of 5-LO(-/-) mice correlated with a lower rate of macrophage ingestion of IgG-H. capsulatum relative to WT macrophages. Conversely, exogenous LTB4 and LTC4 restored macrophage phagocytosis in 5-LO deficient mice. Our results demonstrate that leukotrienes are required to control chronic fungal infection by amplifying both the innate and adaptive immune response during histoplasmosis.
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Adriana
authors.initials: A
authors.lastname: Secatto
authors.forename: Lilian Cataldi
authors.initials: LC
authors.lastname: Rodrigues
authors.forename: Carlos Henrique
authors.initials: CH
authors.lastname: Serezani
authors.forename: Simone Gusmão
authors.initials: SG
authors.lastname: Ramos
authors.forename: Marcelo
authors.initials: M
authors.lastname: Dias-Baruffi
authors.forename: Lúcia Helena
authors.initials: LH
authors.lastname: Faccioli
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Medeiros
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D006658:Histoplasma / Q000276:immunology*; D006660:Histoplasmosis / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D056724:Immunity, Humoral; D007113:Immunity, Innate; D007975:Leukotriene B4 / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D008213:Lymphocyte Activation; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D010587:Phagocytosis; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology* / Q000382:microbiology
chemical_list: D007975:Leukotriene B4; D017997:Leukotriene C4; D009569:Nitric Oxide; D001094:Arachidonate 5-Lipoxygenase