Abstract
BackgroundNitric oxide (NO), a key antimicrobial molecule, was previously shown to exert a dual role in paracoccidioidomycosis, an endemic fungal infection in Latin America. In the intravenous and peritoneal models of infection, NO production was associated with efficient fungal clearance but also with non-organized granulomatous lesions. Because paracoccidioidomycosis is a pulmonary infection, we aimed to characterize the role of NO in a pulmonary model of infection.Methodology/Principal FindingsC57Bl/6 wild type (WT) and iNOS−/− mice were i.t. infected with 1×106 Paracoccidioides brasiliensis yeasts and studied at several post-infection periods. Unexpectedly, at week 2 of infection, iNOS−/− mice showed decreased pulmonary fungal burdens associated with an M2-like macrophage profile, which expressed high levels of TGF-β impaired ability of ingesting fungal cells. This early decreased fungal loads were concomitant with increased DTH reactions, enhanced TNF-α synthesis and intense migration of activated macrophages, CD4+ and CD8+ T cells into the lungs. By week 10, iNOS−/− mice showed increased fungal burdens circumscribed, however, by compact granulomas containing elevated numbers of activated CD4+ T cells. Importantly, the enhanced immunological reactivity of iNOS−/− mice resulted in decreased mortality rates. In both mouse strains, depletion of TNF-α led to non-organized lesions and excessive influx of inflammatory cells into the lungs, but only the iNOS−/− mice showed increased mortality rates. In addition, depletion of CD8+ cells abolished the increased migration of inflammatory cells and decreased the number of TNF-α and IFN-γ CD4+ and CD8+ T cells into the lungs of iNOS−/− mice.Conclusions/SignificanceOur study demonstrated that NO plays a deleterious role in pulmonary paracoccidioidomycosis due to its suppressive action on TNF-α production, T cell immunity and organization of lesions resulting in precocious mortality of mice. It was also revealed that uncontrolled fungal growth can be overcome by an efficient immune response.
Highlights
Phagocytes are important effector cells of innate and adaptative immunity and use several mediators and mechanisms to control pathogen growth
The literature shows that nitric oxide (NO) produced by the enzyme nitric oxide synthase-2 (NOS2 or iNOS) is the major fungicidal component of phagocytic cells
The human paracoccidioidomycosis is believed to be acquired by the respiratory route, our study aimed to characterize the role of NO production in a pulmonary model of infection
Summary
Phagocytes are important effector cells of innate and adaptative immunity and use several mediators and mechanisms to control pathogen growth. The production of nitric oxide (NO) has been shown to be an important microbicidal mechanism of macrophages in the protective immune responses against different pathogens [1,2,3,4]. Besides its action on pathogens viability, there are evidences that NO has an inhibitory effect in the innate and adaptive immunity of hosts. It reduces the antigen-presenting ability of pulmonary dendritic cells, inhibits MHC class II antigen expression, controls the production of cytokines and expression of costimulatory and adhesion molecules [8,9]. Because paracoccidioidomycosis is a pulmonary infection, we aimed to characterize the role of NO in a pulmonary model of infection
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