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J Immunol ; 191(6): 3373-83, 2013 Sep 15.
Article in English | MEDLINE | ID: mdl-23966627

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-1ß 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-1ß. 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.


Subject(s)
Chagas Disease/immunology , Cytoskeletal Proteins/immunology , Disease Resistance/immunology , Inflammasomes/immunology , Interleukin-1beta/immunology , Animals , Apoptosis Regulatory Proteins , CARD Signaling Adaptor Proteins , Carrier Proteins/immunology , Caspase 1/immunology , Flow Cytometry , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein , Oligonucleotide Array Sequence Analysis , Trypanosoma cruzi/immunology
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