XI International Meeting on Paracoccidioidomycosis

XI International Meeting on Paracoccidioidomycosis

Resume:118-1

Oral / Poster

118-1	The absence of ST2 determines increased resistance during early phase of P. brasiliensis experimental infection
Authors:	Fabrine Sales Massafera Tristao (FMRP/USP - Universidade de Sao Paulo) ; Fernanda Agostinho Rocha (FMRP/USP - Universidade de Sao Paulo) ; Fabricio Cesar Dias (FMRP/USP - Universidade de Sao Paulo) ; Jose Carlos Alves Filho (UG - University of GlasgowFMRP/USP - Universidade de Sao Paulo) ; Foo Yoo Liew (UG - University of Glasgow) ; Joao Santana Silva (FMRP/USP - Universidade de Sao Paulo)

Abstract

Introduction and Objective: Paracoccidioides brasiliensis (Pb), a thermally dimorphic fungus, is the causative agent of paracoccidioidomycosis (PCM), one of the most frequent systemic mycosis that affects the rural population in Latin America. Th1 type cytokine responses are critical in the control of PCM, while susceptibility has been linked to the preferential production of the Th2 type responses, such as IL-4, IL-5 and IL-10. ST2, an immunoregulatory protein of the IL-1 receptor (IL-1R) family, exists in two forms that are generated by alternative splicing: as a transmembrane receptor (ST2L) and a cytokine-like soluble form (sST2), characterized by loss of the transmembrane and intracellular domains. Recent findings indicate that ST2L is a Th2 T cell marker. Moreover, the ST2L (recently identified as the receptor for IL-33) is directly stimulated in the presence of antigens, leading to the activation of Th2 cells and the release of Th2- associated cytokines. In this work, we aimed to evaluate the role of ST2 during PCM. Methods and Results: To assess the role of ST2 during the PCM, male Balb/c (wild type, WT) and genetically deficient ST2 (ST2-/-) mice were intravenously inoculated with 1x106 yeast forms of Pb18, a highly virulent P. brasiliensis strain. We found that, unlike WT, ST2-/- mice showed better control of fungal growth and dissemination at 3, 7 and 15 days post infection (dpi). Additionally, at 7 and 15 dpi, the ST2-/- mice showed a less exaggerated and more organized inflammatory response, forming well defined granulomatous lesions. Evaluating the inflammatory infiltrate in the lung tissue, we observed at 15 dpi, an increased frequency of CD11b+CD11c-, CD11b+CD11c+ and CD3+CD4+ cells in ST2-/- mice, suggesting that ST2 is involved in the cell recruitment to the injury site. Besides the increased amount of CD11b+CD11c- cells in the ST2-/- lung, the production of nitric oxide (NO), an important fungicide metabolite, was similar in the lungs from both WT and ST2-/- mice during the early Pb-infection. Conversely, the real-time PCR results showed a diminished nitric oxide synthase (NOS-2) mRNA level in ST2-/- mice at 3 dpi. Moreover, we observed increased levels of IFN-γ and TNF-α in ST2-/- mice at the early phase of infection, suggesting that absence of ST2 enhances the host immune response against P. brasiliensis. Conclusion: Taken together, these preliminary findings suggest that ST2 signaling leads to increased susceptibility during P. brasiliensis infection. Financial support: CNPq

Keyword: fungal infection, immunomodulation, ST2

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