Protective Role of Gamma Interferon in Experimental Pulmonary Paracoccidioidomycosis

Abstract

We have developed a murine model of pulmonary infection byParacoccidioides brasiliensis in which resistance was associated with immunological activities governed by gamma interferon (IFN-γ). To better characterize this model, we measured type 1 and type 2 cytokines in the lungs and investigated the effect of endogenous IFN-γ depletion by monoclonal antibodies in the course of infection of susceptible (B10.A) and resistant (A/Sn) mice. At weeks 4 and 8 after infection, lungs from susceptible animals presented levels of IFN-γ, interleukin-4 (IL-4), IL-5, and IL-10 higher than those in resistant mice. In both mouse strains, neutralization of endogenous IFN-γ induced exacerbation of the pulmonary infection, earlier fungal dissemination to the liver and spleen, impairment of the specific cellular immune response resulting in significantly lower delayed-type hypersensitivity reactions, and increased levels of immunoglobulin G1 (IgG1)- and IgG2b-specific antibodies. Histopathological analysis demonstrated that depletion of IFN-γ changes the focal granulomatous lesions found in the lungs of B10.A and A/Sn mice into coalescent granulomata which destroy the pulmonary architecture. These results suggest that irrespective of the mouse strain, IFN-γ plays a protective role and that this cytokine is one major mediator of resistance against P. brasiliensis infection in mice.

Modulatory effect of prostaglandins on human monocyte activation for killing of high‐ and low‐virulence strains of Paracoccidioides brasiliensis

“…The treatment of intratracheal infected mice with anti-IFN-c monoclonal antibody prevented the clearance of yeast cells from the lungs and promoted their dissemination to the liver and the spleen. 27 Taken together, the present results allow us to hypothesize the mechanisms involved in the early events in the interaction of P. brasiliensis with lung tissue. Contact of the fungus with alveolar macrophages induces an activation process with consequent release of TNF-a, the levels of which will depend on the strain involved.…”

Involvement of extracellular matrix proteins in the course of experimental paracoccidioidomycosis

“…mediated by nitric oxide production (González et al, 2000). In vivo, the importance of this Th1 cytokine has been demonstrated, where both depletion and genetic deficiency of IFN-g led to exacerbated disease (Cano et al, 1998;Souto et al, 2000). In the present work, we observed higher levels of IFN-g in lung homogenates from infected mice when the P. brasiliensis conidia were treated with the various ECM proteins tested during early periods postinfection, especially at day 4.…”

Alveolar macrophages from susceptible mice are more competent than those of resistant mice to control initialParacoccidioides brasiliensisinfection

“…When described, it was demonstrated that during the first weeks of infection, the lung of susceptible mice presented lower fungal loads than that of resistant animals [6]. This pattern was lately reverted when A/J mice develop positive DTH reactions, their lymph node cells secrete IL-2 and IFN-␥, and pulmonary macrophages acquire fungicidal ability [6,8,9]. In susceptible mice, the early control of fungal growth was, however, followed by anergy in DTH reaction, unrestrained increase of yeasts multiplication in the lungs and further dissemination to liver and spleen.…”