Abstract
Fonsecaea pedrosoi is the main etiologic agent of chromoblastomycosis (CBM), one of the most prevalent subcutaneous mycosis in tropical and subtropical countries. CBM is a poorly characterized chronic infection that commonly starts after transcutaneous inoculation of conidia and saprophytic hyphae of F. pedrosoi. Recently, we have shown that unlike conidia, hyphae and muriform cells (the parasitic morphotype) of F. pedrosoi promotes an intense inflammatory response pattern in vivo, which comprises the production of an inflammasome-derived cytokine, IL-1β. Nonetheless, the mechanisms underlying IL-1β production and maturation upon F. pedrosoi infection and its functional output in the course of CBM remains unknown. We show here that F. pedrosoi hyphae, differently from conidia, induce IL-1β secretion in both bone marrow-derived dendritic cells and macrophages. Using inhibitors and knockout cells, we demonstrated that the mechanisms underlying IL-1β production by hyphae-infected macrophages were dependent on dectin-1, -2, and -3 receptors and the Syk-NF-kB signaling pathway. Furthermore, F. pedrosoi promoted a NLRP3-dependent inflammasome activation, which required potassium efflux, reactive oxygen species production, phagolysosomal acidification, and cathepsin B release as triggers. IL-1β processing and release was mediated primarily by caspase-1 and, to a lesser extent, by caspase-8-dependent cleavage. Finally, we showed using a murine CBM model that F. pedrosoi elicits a NLRP3-regulated IL-1β and interleukin-18 release in vivo, but without NLRP3 inflammasome activation interfering in the course of the experimental infection.
Highlights
Chromoblastomycosis (CBM) is a chronic, granulomatous, suppurative, and often debilitating cutaneous and subcutaneous mycosis, caused by dimorphic filamentous fungi belonging to the Dematiaceous family [1,2,3]
To clarify the nature of the pattern recognition receptors (PRRs) that are involved in the F. pedrosoi recognition that led to NF-kBdependent Bone marrow-derived macrophages (BMDMs) priming, we evaluated the transcription of Myd88 and Syk, which are pivotal signal transducers of toll-like receptors (TLRs) and C-type lectin receptors (CLRs), respectively
We demonstrate that the main agent of CBM, F. pedrosoi, activates NLRP3 inflammasomedependent secretion of IL-1β and IL-18 in phagocytes and in vivo
Summary
Chromoblastomycosis (CBM) is a chronic, granulomatous, suppurative, and often debilitating cutaneous and subcutaneous mycosis, caused by dimorphic filamentous fungi belonging to the Dematiaceous family [1,2,3]. Multiple dematiaceous fungi are related to the disease etiology; of these, Fonsecaea pedrosoi and Cladophialophora carrionii are the most frequently identified fungal species in human CBM skin lesions. Little is known about the immune response of the host to infection by F. pedrosoi, it has been credited that an adaptive response mediated by T helper (Th) cell types 1 and 17 might be protective against F. pedrosoi infection [9,10,11] In this scenario, the abrogation of IL-12p35 transcription in human dendritic cells, leading to Th1-deficient development by several Fonsecaea species, and the Th17-mediated response suppression in experimentally infected mice, suggest that this fungal pathogen evade host immune response by complex mechanisms. Besides these cytoplasmic membrane-bound receptors, fungal sensing by cytosolic PRRs, such as NOD-like receptors (NLRs) and AIM2-like receptors, is becoming increasingly apparent
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