STING Signaling Drives Production of Innate Cytokines, Generation of CD8+ T Cells and Enhanced Protection Against Trypanosoma cruzi Infection

Raquel de Souza Vieira, Marilda Savoia Nascimento, Isaú Henrique Noronha, José Ronnie Carvalho Vasconcelos, Luiz Alberto Benvenuti, Glen N. Barber, Niels Olsen Saraiva Câmara, Jorge Kalil, Edecio Cunha-Neto, Rafael Ribeiro Almeida

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

A variety of signaling pathways are involved in the induction of innate cytokines and CD8+ T cells, which are major players in protection against acute Trypanosoma cruzi infection. Previous data have demonstrated that a TBK-1/IRF3-dependent signaling pathway promotes IFN-β production in response to Trypanosoma cruzi, but the role for STING, a main interactor of these proteins, remained to be addressed. Here, we demonstrated that STING signaling is required for production of IFN-β, IL-6, and IL-12 in response to Trypanosoma cruzi infection and that STING absence negatively impacts activation of IRF-dependent pathways in response to the parasite. We reported no significant activation of IRF-dependent pathways and cytokine expression in RAW264.7 macrophages in response to heat-killed trypomastigotes. In addition, we showed that STING is essential for T. cruzi DNA-mediated induction of IFN-β, IL-6, and IL-12 gene expression in RAW264.7 macrophages. We demonstrated that STING-knockout mice have significantly higher parasitemia from days 5 to 8 of infection and higher heart parasitism at day 13 after infection. Although we observed similar heart inflammatory infiltrates at day 13 after infection, IFN-β, IL-12, CXCL9, IFN-γ, and perforin gene expression were lower in the absence of STING. We also showed an inverse correlation between parasite DNA and the expression of CXCL9, IFN-γ, and perforin genes in the hearts of infected animals at day 13 after infection. Finally, we reported that STING signaling is required for splenic IFN-β and IL-6 expression early after infection and that STING deficiency results in lower numbers of splenic parasite-specific IFN-γ and IFN-γ/perforin-producing CD8+ T cells, indicating a pivotal role for STING signaling in immunity to Trypanosoma cruzi.

Original languageEnglish (US)
Article number775346
JournalFrontiers in immunology
Volume12
DOIs
StatePublished - Jan 14 2022
Externally publishedYes

Keywords

  • CD8 T cell
  • IFN-β
  • IL-12
  • IL-6
  • STING
  • Trypanosoma cruzi

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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