3 years ago

A Dectin-1-caspase-8 pathway licenses canonical caspase-1 inflammasome activation and IL-1β release in response to a pathogenic fungus.

Stuart M Levitz, Natália Ketelut-Carneiro, Katherine A Fitzgerald, João Santana da Silva, Sreya Ghosh
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 IL-1β levels. Here we identify an additional pathway for IL-1β production in response to P. brasiliensis infection. P. 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. 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 non-canonical and canonical inflammasomes to coordinate IL-1β production during fungal challenge.

Publisher URL: http://doi.org/10.1093/infdis/jix568

DOI: 10.1093/infdis/jix568

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