A Dectin-1-Caspase-8 Pathway Licenses Canonical Caspase-1 Inflammasome Activation and Interleukin-1β Release in Response to a Pathogenic Fungus.

Abstract

Paracoccidioides brasiliensis is equipped with an arsenal of virulence factors that are crucial for causing infection. Our group previously defined the NLRP3 inflammasome as a mediator of P brasiliensis-induced cell damage recognition and induction of effective Th1 immune responses. However, deficiency of caspase-1 only partially reduced interleukin (IL)-1β levels. In this study, using chemical inhibitors as well as genetically modified mice, we identify an additional pathway for IL-1β production in response to P brasiliensis infection. Paracoccidioides brasiliensis initiated caspase-8-mediated IL-1β production, an event that was necessary for transcriptional priming and posttranslational processing of pro-IL-1β. Caspase-8 synergizes with the canonical NLRP3 inflammasome pathway to control caspase-1 processing and IL-1β maturation, providing a regulatory role for caspase-8 in host resistance to in vivo P brasiliensis infection. Taken together, these findings revealed an important role for caspase-8 in the innate immune response of host cells to P brasiliensis infection, demonstrating a connected network between noncanonical and canonical inflammasomes to coordinate IL-1β production during fungal challenge.