Critical Role of ASC Inflammasomes and Bacterial Type IV Secretion System in Caspase-1 Activation and Host Innate Resistance to Brucella abortus Infection

Pathogens are detected by innate immune receptors that, upon activation, orchestrate an appropriate immune response. Recent studies revealed the intracellular signaling cascades involved in the TLR-initiated immune response to Brucella abortus infection. However, no report has elucidated the role of inflammasome receptors in Brucella recognition. Therefore, we decided to investigate the function of NLRC4, NLRP3, and AIM2 in sensing Brucella. in this study, we showed that NLRC4 is not required to induce caspase-1 activation and further secretion of IL-1 beta by B. abortus in macrophages. in contrast, we determined that AIM2, which senses Brucella DNA, and NLRP3 are partially required for caspase-1 activation and IL-1 beta secretion. Additionally, mitochondrial reactive oxygen species induced by Brucella were implicated in IL-1 beta production. Furthermore, AIM2, NLRP3, ASC, and caspase-1 knockout mice were more susceptible to B. abortus infection than were wild-type animals, suggesting that multiple ASC-dependent inflammasomes contribute to host protection against infection. This protective effect is due to the inflammatory response caused by IL-1 beta and IL-18 rather than pyroptosis, because we observed augmented bacterial burden in IL-1R and IL-18 knockout mice. Finally, we determined that bacterial type IV secretion system VirB and live, but not heat-killed, Brucella are required for full inflammasome activation in macrophages during infection. Taken together, our results indicate that Brucella is sensed by ASC inflammasomes that collectively orchestrate a robust caspase-1 activation and proinflammatory response. the Journal of Immunology, 2013, 190: 3629-3638.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Pecuaria e AbastecimentoInstituto Nacional de Ciencia e Tecnologia de VacinasUniv Fed Minas Gerais, Inst Biol Sci, Dept Biochem & Immunol, BR-31270901 Belo Horizonte, MG, BrazilUniversidade Federal de São Paulo, Ctr Mol & Cellular Therapy, Dept Biol Sci, BR-04044010 São Paulo, BrazilUniv São Paulo, Sch Med Ribeirao Preto São Paulo, Dept Cell Biol, BR-14049900 Ribeirao Preto, BrazilUniversidade Federal de São Paulo, Ctr Mol & Cellular Therapy, Dept Biol Sci, BR-04044010 São Paulo, BrazilWeb of Scienc