Tnf-α and [CD8.sup.+] T cells mediate the beneficial effects of nitric oxide synthase-2 deficiency in pulmonary paracoccidioidomycosis

• Published in: PLoS neglected tropical diseases Vol. 7; no. 8
• Main Authors: Bernardino, Simone, Pina, Adriana, Felonato, Maira, Costa, Tania A, de Araujo, Eliseu Frank, Feriotti, Claudia, Bazan, Silvia Boschi, Keller, Alexandre C, Leite, Katia R.M, Calich, Vera L.G
• Format: Journal Article
• Language: English
• Published: Public Library of Science 01-08-2013
• Subjects: Immune response; Nitric oxide; Paracoccidioidomycosis; Physiological aspects; T cells; Testing
• ISSN: 1935-2727
• DOI: 10.1371/journal.pntd.0002325

Background: Nitric 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 Findings: C57Bl/6 wild type (WT) and [iNOS.sup.-/-] mice were i.t. infected with 1 x [10.sup.6] Paracoccidioides brasiliensis yeasts and studied at several post-infection periods. Unexpectedly, at week 2 of infection, [iNOS.sup.-/-] 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.sup.+] and CD[8.sup.+] T cells into the lungs. By week 10, [iNOS.sup.-/-] mice showed increased fungal burdens circumscribed, however, by compact granulomas containing elevated numbers of activated CD[4.sup.+] T cells. Importantly, the enhanced immunological reactivity of [iNOS.sup.-/-] 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.sup.-/-] mice showed increased mortality rates. In addition, depletion of CD[8.sup.+] cells abolished the increased migration of inflammatory cells and decreased the number of TNF-α and IFN-γ CD[4.sup.+] and CD[8.sup.+] T cells into the lungs of [iNOS.sup.-/-] mice. Conclusions/Significance: Our 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.