Protective Effect of Galectin-1 duringHistoplasma capsulatumInfection Is Associated with Prostaglandin E₂and Nitric Oxide Modulation

Abstract

Histoplasma capsulatum is a dimorphic fungus that develops a yeast-like morphology in host's tissue, responsible for the pulmonary disease histoplasmosis. The recent increase in the incidence of histoplasmosis in immunocompromised patients highlights the need of understanding immunological controls of fungal infections. Here, we describe our discovery of the role of endogenous galectin-1 (Gal-1) in the immune pathophysiology of experimental histoplasmosis. All infected wild-type (WT) mice survived while only 1/3 of Lgals1−/− mice genetically deficient in Gal-1 survived 30 days after infection. Although infected Lgals1−/− mice had increased proinflammatory cytokines, nitric oxide (NO), and elevations in neutrophil pulmonary infiltration, they presented higher fungal load in lungs and spleen. Infected lung and infected macrophages from Lgals1−/− mice exhibited elevated levels of prostaglandin E2 (PGE2, a prostanoid regulator of macrophage activation) and prostaglandin E synthase 2 (Ptgs2) mRNA. Gal-1 did not bind to cell surface of yeast phase of H. capsulatum, in vitro, suggesting that Gal-1 contributed to phagocytes response to infection rather than directly killing the yeast. The data provides the first demonstration of endogenous Gal-1 in the protective immune response against H. capsulatum associated with NO and PGE2 as an important lipid mediator in the pathogenesis of histoplasmosis.

The Sweet-Side of Leukocytes: Galectins as Master Regulators of Neutrophil Function

“…Similarly, Gal-1 treatment in a model of OVA-induced conjunctivitis reduces both pro-inflammatory cytokine production and neutrophil numbers (78). In contrast, Gal-1 KO mice infected intratracheally with Histoplasma capsulatum exhibit an elevated neutrophil pulmonary accumulation that may reflect higher chemokines levels for neutrophils (79).…”

The Role of Collectins and Galectins in Lung Innate Immune Defense

“…In respiratory fungal infections, Gal-1 and Gal-3 play differential roles. Gal-1 modulates prostaglandin E2 and nitric oxide levels in H. capsulatum infection, contributing to phagocyte responses and thus exerting a protective effect ( 102 ). In contrast, Gal-3 −/− mice clear H. capsulatum infection more efficiently than Gal-3 +/+ mice, likely due to a negative regulatory role of Gal-3 on cytokine production by dendritic cells ( 103 ).…”

Galectin-1-deficient mice are protected againstTrypanosoma cruziinfection through altered neutrophil migration and production of reactive oxygen species and nitric oxide

“…In contrast, Gal-1 induces neutrophil migration both in vitro and in vivo in the absence of an inflammatory stimuli (Auvynet et al, 2013). Hence, although the presence of Gal-1 can favor the resolution of adverse inflammatory conditions (Rabinovich et al, 2000; Rodrigues et al, 2016; Seropian et al, 2013), it can be unfavorable in the battle against infection (Davicino et al, 2017). Nevertheless, little is known regarding the role of Gal-1 in parasite infections.…”