Till cell death do us part: The protective role of inflammasome-mediated pyroptosis and genomic DNA recognition during brucellosis

Abstract Brucellosis, a zoonotic disease instigated by the bacteria Brucella, results in chronic inflammatory symptoms. Despite mechanisms utilized by Brucella for immune evasion, some pattern recognition receptors, specifically NOD-like receptors (NLRs), sense Brucella pathogen-associated molecular patterns (PAMPS) and form a multi-protein complex termed the inflammasome. The inflammasome attenuates Brucella pathogenesis through caspase-1 (canonical) or caspase-11 (non-canonical) mediated cleavage of pro-inflammatory cytokines IL-18 & IL-1β. It can also activate inflammatory cell death known as pyroptosis, a mechanism rarely implicated with canonical inflammasome activation in brucellosis. Here, we evaluated in vivo canonical (Asc−/−) and non-canonical (Caspase-11−/−) inflammasome mouse models infected with Brucella abortus and determined that wildtype mice displayed increased survival and recruitment of WBCs with decreased bacteria load in comparison with Asc−/− mice. This indicates that the canonical inflammasome plays a necessary, defensive role against Brucella. Conducting in vitro B. abortus infections in Asc−/− macrophages, we further determined this protective mechanism of canonical inflammasome activation results from the activation of pyroptosis. We also found that the Brucella PAMP genomic (g)DNA instigated a high inflammatory response in wildtype macrophages that was suppressed in Asc−/− and amplified in anti-inflammatory NLR knockouts. This suggests that NLR activation occurs through sensing gDNA and may involve mechanisms of interaction among NLRs. Ultimately, these results suggest a greater importance and continued exploration of pyroptosis and the recognition of gDNA during brucellosis.