Role of the NLRP3 inflammasome in a model of Sporothrix schenckii systemic infection

Author(s)

Amanda Costa Gonçalves

• Document type: Doctoral Thesis
• Press: Araraquara. 2016-12-21.
• Institution: Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara
• Defense date: 2016-12-09
• Advisor: Iracilda Zeppone Carlos

Abstract

Sporotrichosis is a mycosis caused by fungi from the Sporothrix schenckii species complex, whose prototypical member is Sporothrix schenckii sensu stricto. Pattern recognition receptors (PRRs) recognize and respond to pathogen-associated molecular patterns (PAMPs) and shape the following adaptive immune response. A family of PRRs most frequently associated to fungal recognition is the nucleotide-binding oligomerization domain–like receptor (NLR). After recognition of a PAMP, NLR family pyrin domain–containing 3 (NLRP3) binds to apoptosis-associated speck–like protein containing a caspase recruitment domain (ASC) and caspase-1 to form the NLRP3 inflammasome. When activated, this complex promotes maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 that influence the development of the Th17 and Th1 immune responses, respectively. In addition, the NLRP3 inflammassome is responsible for pyroptosis, a highly inflammatory cell death regulated by caspase-1. In this work, we aimed to evaluate the role of the NLRP3 inflammasome to the outcome of the S. schenckii infection using a wild-type mice (WT) and three different knockout mice (KO): NLRP3-/-, ASC-/-, and Casp-1-/-. All the KO mice were more susceptible to the infection than the WT during the S. schenckii infection. Furthermore, the NLRP3 inflammasome seems to be critical to the ex vivo release of NO, IL-1β, IL-18, and IL-17, but not IFN-γ. The S. schenckii infection led to increased activation of caspase-1 and cell death by pyroptosis in WT mice. Also, a role for the inflammasome in shaping the adaptive immune response was suggested by lower frequencies of type 17 helper T (Th17) and Th1/Th17 cells in S. schenckii-infected KO mice. On the other hand, absence of any of the inflammasome components resulted in increased frequency of cytotoxic T cells in this infection. As a whole, our results indicate the NLRP3 inflammasome links the innate recognition of S. schenckii to the adaptive immune response, thus contributing to protective response in the infection by this fungus. (AU)

• FAPESP's process: 13/03190-5 - Role of the inflammasome in to fungal infections induced by Sporothrix schenckii
• Grantee: Amanda Costa Gonçalves
• Support Opportunities: Scholarships in Brazil - Doctorate