Interferon-gamma and tumor necrosis factor-alpha determine resistance to Paracoccidioides brasiliensis infection in mice

To investigate the role of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the resistance to Paracoccidioides brasiliensis (Pb) infection, mice with homologous disruption of the IFN-gamma (GKO) or TNF-alpha receptor p55 (p55KO) were infected. with the parasite. GKO and p5 5KO, but not wild-type (WT) mice, were unable to control the growth of yeas t cells and the mice succumbed to infection by days 16 and 90 after infecti on, respectively. Typical inflammatory granulomas were found only in WT mic e. In contrast, knockout mice presented an inflammatory infiltrate composed of a few neutrophils, mononuclear, epithelioid, and multinuclear giant cel ls forming incipient granulomas in GKO mice and without granuloma formation in p55KO mice. Besides, both groups of knockout mice exhibited elevated nu mbers of yeast forms in agreement with colony-forming unit counts in organs . Compared with WT, splenocytes from infected GKO mice cultured with the Pb Fl fraction produced lower TNF-alpha levels, whereas leukocytes from infec ted p55KO mice produced similar amounts of TNF-alpha but higher levels of I FN-gamma. Moreover, splenocytes from infected WT mice produced higher level s of nitric oxide (NO) resulting in a lower T-cell proliferative response t o Con A than uninfected WT, or infected p55KO and GKO mice. On the contrary , the addition of IFN-gamma to splenocytes from infected GKO mice resulted in higher NO production and lower T cell proliferation. Taken together, the se findings suggests that endogenous TNF-alpha, acting through the p55 rece ptor, and IFN-gamma mediate resistance to Pb infection and induce NO produc tion that determines marked T cell unresponsiveness.