Apoptosis-Associated Speck-like Protein Containing a Caspase Recruitment Domain Inflammasomes Mediate IL-1 beta Response and Host Resistance to Trypanosoma cruzi Infection

Author(s):Show less -

Silva, Grace Kelly ^{[1, 2, 3]} ; Costa, Renata Sesti ^[3] ; Silveira, Tatiana Nunes ^{[1, 2]} ; Caetano, Braulia Costa ; Horta, Catarina Veltrini ^{[1, 2]} ; Salazar Gutierrez, Fredy Roberto ^[4] ; da Matta Guedes, Paulo Marcos ^[5] ; Andrade, Warrison Athanasio ^{[6, 7]} ; De Niz, Mariana ^{[8, 9]} ; Gazzinelli, Ricardo Tostes ^{[6, 7]} ; Zamboni, Dario Simoes ^{[1, 2]} ; Silva, Joao Santana ^[3]

Affiliation

^[1] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA 01655 - USA

^[2] Univ Sao Paulo, Dept Cellular Biol, Ribeirao Preto Med Sch, BR-14049900 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Dept Biochem & Immunol, Ribeirao Preto Med Sch, BR-14049900 Sao Paulo - Brazil

^[4] Univ Antonio Narino, Sch Med, Bogota 110231 - Colombia

^[5] Univ Fed Rio Grande do Norte, Dept Microbiol & Parasitol, BR-59072970 Natal, RN - Brazil

^[6] Univ Fed Minas Gerais, Dept Bioquim & Imunol, BR-31270901 Belo Horizonte, MG - Brazil

^[7] Fundacao Oswaldo Cruz, Ctr Pesquisas Rene Rachou, BR-30190002 Belo Horizonte, MG - Brazil

^[8] Univ Bern, Inst Cell Biol, CH-3012 Bern - Switzerland

^[9] Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res, E-08036 Barcelona - Spain

• Document type: Journal article
• Source: JOURNAL OF IMMUNOLOGY; v. 191, n. 6, p. 3373-3383, SEP 15 2013.
• Web of Science Citations: 41

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-1 beta 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-1 beta. 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. (AU)

• FAPESP's process: 10/50959-4 - Determination of murine loci and genes responsible for the natural resistance to Trypanosoma cruzi infection
• Grantee: Dario Simões Zamboni
• Support Opportunities: Regular Research Grants
• FAPESP's process: 07/53940-0 - The regulatory T cells and TH17 in the immune response against infections, tumors and autoimmune diseases
• Grantee: João Santana da Silva
• Support Opportunities: Research Projects - Thematic Grants