title: Apoptosis-associated speck-like protein containing a caspase recruitment domain inflammasomes mediate IL-1β response and host resistance to Trypanosoma cruzi infection.
abstract: The innate immune response to Trypanosoma cruzi infection comprises several pattern recognition receptors (PRRs), including TLR-2, -4, -7, and -9, as well as the cytosolic receptor Nod1. However, there are additional PRRs that account for the host immune responses to T. cruzi. In this context, the nucleotide-binding oligomerization domain-like receptors (NLRs) that activate the inflammasomes are candidate receptors that deserve renewed investigation. Following pathogen infection, NLRs form large molecular platforms, termed inflammasomes, which activate caspase-1 and induce the production of active IL-1β and IL-18. In this study, we evaluated the involvement of inflammasomes in T. cruzi infection and demonstrated that apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) inflammasomes, including NLR family, pyrin domain-containing 3 (NLRP3), but not NLR family, caspase recruitment domain-containing 4 or NLR family, pyrin domain-containing 6, are required for triggering the activation of caspase-1 and the secretion of IL-1β. The mechanism by which T. cruzi mediates the activation of the ASC/NLRP3 pathway involves K⁺ efflux, lysosomal acidification, reactive oxygen species generation, and lysosomal damage. We also demonstrate that despite normal IFN-γ production in the heart, ASC⁻/⁻ and caspase-1⁻/⁻ infected mice exhibit a higher incidence of mortality, cardiac parasitism, and heart inflammation. These data suggest that ASC inflammasomes are critical determinants of host resistance to infection with T. cruzi.
authors: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil.
authors: Grace Kelly
authors: GK
authors: Silva
authors: Renata Sesti
authors: RS
authors: Costa
authors: Tatiana Nunes
authors: TN
authors: Silveira
authors: Braulia Costa
authors: BC
authors: Caetano
authors: Catarina Veltrini
authors: CV
authors: Horta
authors: Fredy Roberto Salazar
authors: FR
authors: Gutierrez
authors: Paulo Marcos da Matta
authors: PM
authors: Guedes
authors: Warrison Athanásio
authors: WA
authors: Andrade
authors: Mariana
authors: M
authors: De Niz
authors: Ricardo Tostes
authors: RT
authors: Gazzinelli
authors: Dario Simões
authors: DS
authors: Zamboni
authors: João Santana
authors: JS
authors: Silva
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000276:immunology; D020170:Caspase 1 / Q000276:immunology; D014355:Chagas Disease / Q000276:immunology*; D003598:Cytoskeletal Proteins / Q000276:immunology*; D060467:Disease Resistance / Q000276:immunology*; D005434:Flow Cytometry; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020411:Oligonucleotide Array Sequence Analysis; D014349:Trypanosoma cruzi / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D020170:Caspase 1