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 ... show 2 more
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Keywords
Apoptosis Regulatory Proteins
Carrier Proteins
Caspase 1
Chagas Disease
Cytoskeletal Proteins
Disease Resistance
Flow Cytometry
Inflammasomes
Interleukin-1beta
Mice
Mice, Inbred C57BL
Mice, Knockout
Oligonucleotide Array Sequence Analysis
Trypanosoma cruzi
Immunity
Immunology of Infectious Disease
Parasitic Diseases
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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