University of Massachusetts Medical School Faculty Publications

Title

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

UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Date

9-15-2013

Document Type

Article

Medical Subject Headings

Animals; 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

Disciplines

Immunity | Immunology of Infectious Disease | Parasitic Diseases

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.

Rights and Permissions

Citation: 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

Related Resources

Link to Article in PubMed

PubMed ID

23966627