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Apoptosis-associated speck-like protein containing a caspase recruitment domain inflammasomes mediate IL-1beta response and host resistance to Trypanosoma cruzi infection

Silva, Grace Kelly
Costa, Renata Sesti
Silveira, Tatiana Nunes
Caetano, Braulia C.
Horta, Catarina Veltrini
Gutierrez-Salazar, Fredy Roberto
da Matta Guedes, Paulo Marcos
Andrade, Warrison A.
De Niz, Mariana
Gazzinelli, Ricardo T
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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-1beta 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-1beta. 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.

Source

J Immunol. 2013 Sep 15;191(6):3373-83. doi: 10.4049/jimmunol.1203293. Epub 2013 Aug 21. Link to article on publisher's site

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10.4049/jimmunol.1203293
PubMed ID
23966627
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