In Pulmonary Paracoccidioidomycosis IL-10 Deficiency Leads to Increased Immunity and Regressive Infection without Enhancing Tissue Pathology.

Background: Cellular 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 Findings: Wild 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/Significance: Our 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. Author Summary: Paracoccidioidomycosis, the most important deep mycosis from Latin America, is acquired by inhalation of fungal spores. The pulmonary infection can remain as a quiescent infection or evolve to overt, life-threatening disease. Immunoprotection is mainly mediated by Th1 lymphocytes secreting IFN- γ, the most important macrophage activating cytokine. It is well established that the severe forms of infection are associated with elevated production of anti-inflammatory or suppressive cytokines such as IL-10. However, direct approaches investigating the role of this cytokine in pulmonary paracoccidioidomycosis were never employed. This led us to investigate the innate and adaptive aspects of immunity in pulmonary paracoccidioidomycosis using IL-10-deficient mice in comparison with their IL-10-normal counterparts. We verified that IL-10 absence leads to a regressive disease, resulting in reduced mortality rates of infected mice. 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. [ABSTRACT FROM AUTHOR]