5-Lipoxygenase Deficiency Impairs Innate and Adaptive Immune Responses during Fungal Infection

Adriana Secatto,Carlos Henrique Serezani,Alexandra I Medeiros,Marcelo Dias-Baruffi,Lilian Cataldi Rodrigues,Lúcia Helena Faccioli,Simone Gusmão Ramos,Robin Charles May

doi:10.1371/journal.pone.0031701

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.

Highlights

Histoplasma capsulatum is a dimorphic, facultative, intracellular fungal pathogen ingested by resident cells such as alveolar macrophages and dendritic cells and by neutrophils when these inflammatory cells are recruited to the site of infection
The 5-LO-activating protein (FLAP) activates 5-LO that oxygenates arachidonic acid (AA) to form LTA4 [6]. This intermediate can be hydrolized to form LTB4 by LTA4 hydrolase or LTC4 synthase, which catalyzes the conjugation with glutathione to form the LTC4 that will be formed into LTD4 and LTE4, collectively known as cysteinyl LTs (CysLTs) [7]. 5-LO metabolites are known for their ability to function as neutrophil chemoattractants (LTB4) and for their effects on smooth muscle contraction during asthma (CysLTs)
To determine if LTs are required for host defense during H. capsulatum infection, we initially sought to investigate whether LTs are produced in the lungs of WT sv129-infected animals

Summary

Introduction

Histoplasma capsulatum is a dimorphic, facultative, intracellular fungal pathogen ingested by resident cells such as alveolar macrophages and dendritic cells and by neutrophils when these inflammatory cells are recruited to the site of infection. H. capsulatum-infected 5-LO2/2 mice showed an intense influx of neutrophils and an impaired ability to generate and recruit effector T cells to the lung.

Results

Conclusion