title: Critical role of ASC inflammasomes and bacterial type IV secretion system in caspase-1 activation and host innate resistance to Brucella abortus infection.
abstract: 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-1β 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-1β secretion. Additionally, mitochondrial reactive oxygen species induced by Brucella were implicated in IL-1β 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-1β 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.
authors: Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901 Brazil.
authors: Marco Tulio R
authors: MT
authors: Gomes
authors: Priscila C
authors: PC
authors: Campos
authors: Fernanda S
authors: FS
authors: Oliveira
authors: Patricia P
authors: PP
authors: Corsetti
authors: Karina R
authors: KR
authors: Bortoluci
authors: Larissa D
authors: LD
authors: Cunha
authors: Dario S
authors: DS
authors: Zamboni
authors: Sergio C
authors: SC
authors: Oliveira
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D058947:Bacterial Secretion Systems; D002003:Brucella abortus / Q000276:immunology* / Q000378:metabolism*; D002006:Brucellosis / Q000276:immunology* / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004269:DNA, Bacterial / Q000378:metabolism; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D020022:Genetic Predisposition to Disease; D006099:Granuloma / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007113:Immunity, Innate; D058847:Inflammasomes; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D058947:Bacterial Secretion Systems; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; C498534:Pycard protein, mouse; D017382:Reactive Oxygen Species; D017472:Receptors, Interleukin-1; D020170:Caspase 1