The leukotriene B₄/BLT₁ axis is a key determinant in susceptibility and resistance to histoplasmosis.
The bioactive lipid mediator leukotriene B4 (LTB4) greatly enhances phagocyte antimicrobial functions against a myriad of pathogens. In murine histoplasmosis, inhibition of the LT-generating enzyme 5-lypoxigenase (5-LO) increases the susceptibility of the host to infection. In this study, we investigated whether murine resistance or susceptibility to Histoplasma capsulatum infection is associated with leukotriene production and an enhancement of in vivo and/or in vitro antimicrobial effector function. We show that susceptible C57BL/6 mice exhibit a higher fungal burden in the lung and spleen, increased mortality, lower expression levels of 5-LO and leukotriene B4 receptor 1 (BLT1) and decreased LTB4 production compared to the resistant 129/Sv mice. Moreover, we demonstrate that endogenous and exogenous LTs are required for the optimal phagocytosis of H. capsulatum by macrophages from both murine strains, although C57BL/6 macrophages are more sensitive to the effects of LTB4 than 129/Sv macrophages. Therefore, our results provide novel evidence that LTB4 production and BLT1 signaling are required for a histoplasmosis-resistant phenotype.
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
Adriana
A
Secatto
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
Elyara Maria
EM
Soares
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
Gisele Aparecida
GA
Locachevic
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
Patricia Aparecida
PA
Assis
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil ; Departamento de Odontopediatria, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
Francisco Wanderlei Garcia
FW
Paula-Silva
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Carlos Henrique
CH
Serezani
Departamento de Ciências Biológicas, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista "Júlio de Mesquita Filho", Araraquara, São Paulo, Brazil.
Alexandra Ivo
AI
de Medeiros
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
Lúcia Helena
LH
Faccioli
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000276:immunology; D004198:Disease Susceptibility; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000276:immunology; D006658:Histoplasma / Q000276:immunology* / Q000472:pathogenicity; D006660:Histoplasmosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000662:veterinary*; D058507:Host Specificity; D054884:Host-Pathogen Interactions; D007975:Leukotriene B4 / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000187:drug effects; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000276:immunology*; D012376:Rodent Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000382:microbiology
D004791:Enzyme Inhibitors; C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase