Participation of the inflammasome NLRP3 and cytokines from the IL-1 family in the infammatory response induced by the pathogenic fungi Paracoccidioides brasiliensis and Candida albicans

Abstract

Infections caused by fungi are currently amongst the most life-threatening diseases. Among the systemic mycoses , Candida albicans infection in characterized mainly as an opportunistic infection, while paracoccidioidomycosis (PCM), caused by Paracoccidioides brasiliensis , is the major cause of systemic mycosis affecting immunocompent individuals in Brazil. However, studies on the immune response against these infections , particularly PCM, are still scarce. The inflammatory response is extremely important to control the disease; nevertheless, exacerbation of this response can cause tissue damage and imbalance of the immune response. The inflammatory response is initiated by the recognition of fungal cells through receptors expressed by cells of the innate immune system. Recently, a new family of receptors (NOD-like receptors or NLRs) involved in the recognition of molecules expressed by pathogens and stress signals produced during infection or cellular damage was described. Some NLRs participate in the assembling of a multiproteic complex called inflammasoma that activate caspase-1, which is responsible for the production of the active forms of two important cytokines: IL-1beta and IL-18. Among NLRs, the NLRP3 was associated with the recognition of pathogenic fungi such as Candida albicans and Aspergillus fumigatus in experimental models, working in association with TLR2 and dectin-1. There are still no data supporting a role for this receptor in P. brasiliensis infection. However, some evidences suggest the involvement of NLRs in PCM, mostly in the production of IL-1beta and IL-18, cytokines that are found in lesions and in peripheral blood of PCM patients. In addition, although studies in experimental models indicate that NLRs participate in the immune response against C. albicans, data with human cells are still quite inconsistent. This study aims to investigate a possible involvement of NLRP3 in the activation of the inflammatory response of macrophages and dendritic cells in response to P. brasiliensis and to determine whether this receptor is involved in the development of the adaptive response after the stimulus by P. brasiliensis and C. albicans. Therefore, this study could contribute to expand our knowledge about the function of the NLRs and their possible role in the initial response against pathogens, not only P. brasiliensis, but in other systemic fungal infections. (AU)