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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Apoptosis-Associated Speck-like Protein Containing a Caspase Recruitment Domain Inflammasomes Mediate IL-1 beta Response and Host Resistance to Trypanosoma cruzi Infection

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Silva, Grace Kelly [1, 2, 3] ; Costa, Renata Sesti [3] ; Silveira, Tatiana Nunes [2, 1] ; Caetano, Braulia Costa ; Horta, Catarina Veltrini [1, 2] ; Salazar Gutierrez, Fredy Roberto [4] ; da Matta Guedes, Paulo Marcos [5] ; Andrade, Warrison Athanasio [6, 7] ; De Niz, Mariana [8, 9] ; Gazzinelli, Ricardo Tostes [6, 7] ; Zamboni, Dario Simoes [1, 2] ; Silva, Joao Santana [3]
Total Authors: 12
[1] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA 01655 - USA
[2] Univ Sao Paulo, Dept Cellular Biol, Ribeirao Preto Med Sch, BR-14049900 Sao Paulo - Brazil
[3] Univ Sao Paulo, Dept Biochem & Immunol, Ribeirao Preto Med Sch, BR-14049900 Sao Paulo - Brazil
[4] Univ Antonio Narino, Sch Med, Bogota 110231 - Colombia
[5] Univ Fed Rio Grande do Norte, Dept Microbiol & Parasitol, BR-59072970 Natal, RN - Brazil
[6] Univ Fed Minas Gerais, Dept Bioquim & Imunol, BR-31270901 Belo Horizonte, MG - Brazil
[7] Fundacao Oswaldo Cruz, Ctr Pesquisas Rene Rachou, BR-30190002 Belo Horizonte, MG - Brazil
[8] Univ Bern, Inst Cell Biol, CH-3012 Bern - Switzerland
[9] Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res, E-08036 Barcelona - Spain
Total Affiliations: 9
Document type: Journal article
Source: JOURNAL OF IMMUNOLOGY; v. 191, n. 6, p. 3373-3383, SEP 15 2013.
Web of Science Citations: 41

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. (AU)

FAPESP's process: 10/50959-4 - Determination of murine loci and genes responsible for the natural resistance to Trypanosoma cruzi infection
Grantee:Dario Simões Zamboni
Support type: Regular Research Grants
FAPESP's process: 07/53940-0 - The regulatory T cells and TH17 in the immune response against infections, tumors and autoimmune diseases
Grantee:João Santana da Silva
Support type: Research Projects - Thematic Grants