Abstract
Paracoccidioides brasiliensis is the etiologic agent of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis that is geographically confined to Latin America. The pro-inflammatory cytokine IL-1β that is mainly derived from the activation of the cytoplasmic multiprotein complex inflammasome is an essential host factor against opportunistic fungal infections; however, its role in infection with a primary fungal pathogen, such as P. brasiliensis, is not well understood. In this study, we found that murine bone marrow-derived dendritic cells responded to P. brasiliensis yeast cells infection by releasing IL-1β in a spleen tyrosine kinase (Syk), caspase-1 and NOD-like receptor (NLR) family member NLRP3 dependent manner. In addition, P. brasiliensis-induced NLRP3 inflammasome activation was dependent on potassium (K+) efflux, reactive oxygen species production, phagolysosomal acidification and cathepsin B release. Finally, using mice lacking the IL-1 receptor, we demonstrated that IL-1β signaling has an important role in killing P. brasiliensis by murine macrophages. Altogether, our results demonstrate that the NLRP3 inflammasome senses and responds to P. brasiliensis yeast cells infection and plays an important role in host defense against this fungus.
Highlights
Paracoccidioides brasiliensis is a thermally dimorphic fungus that causes paracoccidioidomycosis (PCM), a systemic granulomatous mycosis that is endemic to South America, especially Brazil, Argentina, Venezuela and Colombia [1,2]
We demonstrate that P. brasiliensis is sensed by the NLRP3 inflammasome, a cytoplasmatic multiprotein complex that lead to the processing and secretion of IL-1b
To investigate whether P. brasiliensis could induce IL-1b secretion, murine bone marrow-derived macrophages (BMDMs) and BMDCs were infected with P. brasiliensis yeast cells for 24 h, and mature IL-1b production was measured in the culture supernatants using enzyme-linked immunosorbent assay (ELISA)
Summary
Paracoccidioides brasiliensis is a thermally dimorphic fungus that causes paracoccidioidomycosis (PCM), a systemic granulomatous mycosis that is endemic to South America, especially Brazil, Argentina, Venezuela and Colombia [1,2]. P. brasiliensis grows as saprophytic mycelia that produce infective conidia propagules, which are inhaled into the lungs where the fungus transitions to the pathogenic yeast form. This step is essential for the successful establishment of infection [4,5,6]. Innate immune cells, such as resident macrophages and dendritic cells, are the first line of defense that interact with P. brasiliensis cells [7] Such activity is based on the recognition of conserved microbial structures, known as pathogenassociated molecular patterns (PAMPs), by germline-encoded pattern recognition receptors (PRRs) [8,9]. The first priming signal relies on PAMP recognition by PRRs, which directs
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