Abstract | BACKGROUND: METHODOLOGY/PRINCIPAL FINDINGS: C57Bl/6 wild type (WT) and iNOS(-/-) mice were i.t. infected with 1×10(6) Paracoccidioides brasiliensis yeasts and studied at several post- infection periods. Unexpectedly, at week 2 of infection, iNOS(-/-) 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(+) and CD8(+) T cells into the lungs. By week 10, iNOS(-/-) mice showed increased fungal burdens circumscribed, however, by compact granulomas containing elevated numbers of activated CD4(+) T cells. Importantly, the enhanced immunological reactivity of iNOS(-/-) 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(-/-) mice showed increased mortality rates. In addition, depletion of CD8(+) cells abolished the increased migration of inflammatory cells and decreased the number of TNF-α and IFN-γ CD4(+) and CD8(+) T cells into the lungs of iNOS(-/-) 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.
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Authors | Simone Bernardino, Adriana Pina, Maíra Felonato, Tânia A Costa, Eliseu Frank de Araújo, Cláudia Feriotti, Silvia Boschi Bazan, Alexandre C Keller, Katia R M Leite, Vera L G Calich |
Journal | PLoS neglected tropical diseases
(PLoS Negl Trop Dis)
Vol. 7
Issue 8
Pg. e2325
( 2013)
ISSN: 1935-2735 [Electronic] United States |
PMID | 23936574
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Tumor Necrosis Factor-alpha
- Nitric Oxide Synthase Type II
- Nos2 protein, mouse
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Topics |
- Animals
- CD8-Positive T-Lymphocytes
(immunology)
- Colony Count, Microbial
- Granuloma
(immunology, microbiology, pathology)
- Humans
- Lung
(microbiology, pathology)
- Lung Diseases, Fungal
(immunology, pathology)
- Macrophages
(immunology)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Nitric Oxide Synthase Type II
(deficiency, metabolism)
- Paracoccidioides
(immunology)
- Paracoccidioidomycosis
(immunology, pathology)
- Survival Analysis
- Time Factors
- Tumor Necrosis Factor-alpha
(immunology)
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