Abstract
BackgroundCellular immunity is the main defense mechanism in paracoccidioidomycosis (PCM), the most important systemic mycosis in Latin America. Th1 immunity and IFN-γ activated macrophages are fundamental to immunoprotection that is antagonized by IL-10, an anti-inflammatory cytokine. Both in human and experimental PCM, several evidences indicate that the suppressive effect of IL-10 causes detrimental effects to infected hosts. Because direct studies have not been performed, this study was aimed to characterize the function of IL-10 in pulmonary PCM.Methodology/Principal FindingsWild type (WT) and IL-10−/− C57BL/6 mice were used to characterize the role of IL-10 in the innate and adaptive immunity against Paracoccidioides brasiliensis (Pb) infection. We verified that Pb-infected peritoneal macrophages from IL-10−/− mice presented higher phagocytic and fungicidal activities than WT macrophages, and these activities were associated with elevated production of IFN-γ, TNF-α, nitric oxide (NO) and MCP-1. For in vivo studies, IL-10−/− and WT mice were i.t. infected with 1×106 Pb yeasts and studied at several post-infection periods. Compared to WT mice, IL-10−/− mice showed increased resistance to P. brasiliensis infection as determined by the progressive control of pulmonary fungal loads and total clearance of fungal cells from dissemination organs. This behavior was accompanied by enhanced delayed-type hypersensitivity reactions, precocious humoral immunity and controlled tissue pathology resulting in increased survival times. In addition, IL-10−/− mice developed precocious T cell immunity mediated by increased numbers of lung infiltrating effector/memory CD4+ and CD8+ T cells. The inflammatory reactions and the production of Th1/Th2/Th17 cytokines were reduced at late phases of infection, paralleling the regressive infection of IL-10−/− mice.Conclusions/SignificanceOur work demonstrates for the first time that IL-10 plays a detrimental effect to pulmonary PCM due to its suppressive effect on the innate and adaptive immunity resulting in progressive infection and precocious mortality of infected hosts.
Highlights
The clinical significance of fungal infections has increased dramatically in the past decades
This better disease outcome was associated with precocious and enhanced mechanisms of innate and adaptive immunity that allow the control of fungal growth without excessive inflammatory reactions and harmful tissue pathology
These evidences on the detrimental effects of IL-10 to pulmonary paracoccidioidomycosis suggest that therapeutic measures aimed to control IL-10 production or activity could exert a protective effect to this severe fungal pathology
Summary
The clinical significance of fungal infections has increased dramatically in the past decades. Th17 cells have been associated with immunoprotection or excessive tissue pathology, whereas regulatory T cells (Treg) have been shown to play an essential role in the control of innate and adaptive immunity to fungal infections [4,5]. To the human disease, susceptibility was linked to depressed cellular immunity associated with enhanced IL-10 production and absence of IFN- c synthesis [7,8,9]. Th1 immunity and IFN-c activated macrophages are fundamental to immunoprotection that is antagonized by IL-10, an anti-inflammatory cytokine. Both in human and experimental PCM, several evidences indicate that the suppressive effect of IL-10 causes detrimental effects to infected hosts. Because direct studies have not been performed, this study was aimed to characterize the function of IL-10 in pulmonary PCM
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have