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2030-12-31
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APOPTOSIS-ASSOCIATED SPECK-LIKE PROTEIN CONTAINING A CASPASE RECRUITMENT DOMAIN INFLAMMASOMES MEDIATE IL-1 BETA RESPONSE AND HOST RESISTANCE TO TRYPANOSOMA CRUZI INFECTION
Autor
Afiliación
Department of Biochemistry and Immunology. Ribeirão Preto Medical School. University of São Paulo. Ribeirão Preto, SP, Brazil / Department of Cellular Biology. Ribeirão Preto Medical School. University of São Paulo. Ribeirão Preto, SP, Brazil.
Department of Biochemistry and Immunology. Ribeirão Preto Medical School. University of São Paulo. Ribeirão Preto, SP, Brazil.
Department of Cellular Biology. Ribeirão Preto Medical School. University of São Paulo. Ribeirão Preto, SP, Brazil.
Department of Cellular Biology. Ribeirão Preto Medical School. University of São Paulo. Ribeirão Preto, SP, Brazil.
Departamento de Microbiologia e Parasitologia. Universidade Federal do Rio Grande do Norte. Natal, RN, Brazil.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Medical School. Worcester, MA, USA / Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brazil / Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Belo Horizonte, MG, Brazil.
Institute of Cell Biology. University of Bern. Bern. Switzerland/Barcelona Center for International Health Research. Barcelona, Spain.
Department of Cellular Biology. Ribeirão Preto Medical School. University of São Paulo. Ribeirão Preto, São Paulo, Brazil.
Department of Cellular Biology. Ribeirão Preto Medical School. University of São Paulo. Ribeirão Preto, SP, Brazil.
Department of Biochemistry and Immunology. Ribeirão Preto Medical School. University of São Paulo. Ribeirão Preto, SP, Brazil.
Department of Cellular Biology. Ribeirão Preto Medical School. University of São Paulo. Ribeirão Preto, SP, Brazil.
Department of Cellular Biology. Ribeirão Preto Medical School. University of São Paulo. Ribeirão Preto, SP, Brazil.
Departamento de Microbiologia e Parasitologia. Universidade Federal do Rio Grande do Norte. Natal, RN, Brazil.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Medical School. Worcester, MA, USA / Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brazil / Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Belo Horizonte, MG, Brazil.
Institute of Cell Biology. University of Bern. Bern. Switzerland/Barcelona Center for International Health Research. Barcelona, Spain.
Department of Cellular Biology. Ribeirão Preto Medical School. University of São Paulo. Ribeirão Preto, São Paulo, Brazil.
Department of Cellular Biology. Ribeirão Preto Medical School. University of São Paulo. Ribeirão Preto, SP, Brazil.
Resumen en ingles
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-1 beta 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-1 beta. 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-gamma 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.
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