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

Publication Date

9-15-2013

Document Type

Article

Subjects

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.

DOI of Published Version

10.4049/jimmunol.1203293

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

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Journal of immunology (Baltimore, Md. : 1950)

PubMed ID

23966627

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