The Leukotriene B4/BLT1 Axis Is a Key Determinant in Susceptibility and Resistance to Histoplasmosis

Adriana Secatto,Gisele Aparecida Locachevic,Carlos Henrique Serezani,Alexandra Ivo De Medeiros,Patricia Aparecida Assis,Francisco Wanderlei Garcia Paula-Silva,Elyara Maria Soares,Lúcia Helena Faccioli

doi:10.1371/journal.pone.0085083

Abstract

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.

Highlights

Histoplasmosis is caused by the dimorphic pathogenic fungus Histoplasma capsulatum, and infection occurs when microconidia are inhaled and transformed into yeast in the lung environment [1,2]
Using pharmacologic and genetic approaches, we demonstrated that endogenous LTs augment the susceptibility of mice to primary and secondary H. capsulatum infections by amplifying fungal clearance and the production of the proinflammatory cytokines IL-12 and IFN-c and the microbicidal molecule nitric oxide (NO)
C57BL/6 mice are more susceptible to H. capsulatum infection than 129/Sv mice

Summary

Introduction

Histoplasmosis is caused by the dimorphic pathogenic fungus Histoplasma capsulatum, and infection occurs when microconidia are inhaled and transformed into yeast in the lung environment [1,2]. The data from our laboratory demonstrate that 129/Sv mice are more resistant to H. capsulatum infection compared to C57BL/6 mice [7,27]. We sought to investigate whether susceptibility and resistance to H. capsulatum infection are associated with differential LT production and/or action in these two animal strains.

Results

Conclusion