Short-Chain Fatty Acids Modulate the Response of Murine Macrophages and Dendritic Cells to <em>Paracoccidioides brasiliensis</em>   — ASN Events
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  3. Short-Chain Fatty Acids Modulate the Response of Murine Macrophages and Dendritic Cells to Paracoccidioides brasiliensis  

Short-Chain Fatty Acids Modulate the Response of Murine Macrophages and Dendritic Cells to Paracoccidioides brasiliensis   (#183)

Aimê Stefany A da Fonseca 1 , Euller F Lopes 1 , Estevão M Moraes 1 , ALDO H TAVARES 1
  1. University of Brasilia, Brasilia, DF, Brazil

Introduction:Short-chain fatty acids (SCFAs) are the main metabolites produced by the gut microbiota and exert crucial roles in the maintenance of systemic homeostasis. Their role in pathogen-host interactions involves immunomodulatory effects, particularly on phagocytic cells. Reports on bacterial and fungal infections show modulation of cytokine production and microbicidal activity of phagocytes upon SCFAs treatment. However, there are still no reports on the effects of SCFAs on phagocytes infected with Paracoccidioides brasiliensis, the major aetiologic agent of the most prevalent systemic mycosis in Latin America Paracoccidioidomycosis (PCM). Therefore, this study aimed to evaluate the immunomodulatory role of SCFAs on phagocytes infected with P. brasiliensis. Methods: RAW264.7 macrophages and bone Marrow-derived macrophages and dendritic cells were treated with 20 or 40 mM of sodium acetate, propionate, or butyrate and infected in vitro with P. brasiliensis yeasts. The production of cytokines was assessed using ELISA after 24 and 48 hours of co-culture. To assess the role of PI3K/AKT and NFkB/NLRP3 inflammassome pathways in the modulation of cytokine secretion, the inhibitors Wortmannin and BAY11-7082 were employed. Additionally, the fungicidal capacity of the macrophages and the role of phagolysosome acidification in this process were evaluated by CFU counting and the use of Bafilomycin Results: Infected phagocytes treated with SCFAs showed inhibition of TNF-α and IL-10 secretion concomitantly with increased IL-1β production when compared to untreated groups, a cytokine profile associated with host protection against P. brasiliensis. Interestingly, IL1β enhanced secretion induced by SCFAs was abrogated by Wortmannin and BAY11- 7082, suggesting the role of PI3K/AKT and NFkB/NLRP3 inflammassome pathways in this process. Furthermore, SCFAs treatment promoted enhanced macrophage fungicidal activity dependent on phagolysosome acidification. Conclusion: Our preliminary results show an immunomodulatory role for SCFAs in phagocytes infected with P. brasiliensis, prompting further evaluation using the murine model for pulmonary PCM.