Brucella abortus Triggers a cGAS-Independent STING Pathway to Induce Host Protection That Involves Guanylate-Binding Proteins and Inflammasome Activation

Miriam M.Costa Franco, Fernanda Marim, Erika S. Guimarães, Natan R.G. Assis, Daiane M. Cerqueira, Juliana Alves-Silva, Jerome Harms, Gary Splitter, Judith Smith, Thirumala Devi Kanneganti, Nina M.G.P. De Queiroz, Delia Gutman, Glen N Barber, Sergio C. Oliveira

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Immunity against microbes depends onrecognition ofpathogen-associated molecular patternsbyinnate receptors. Signaling pathways triggered by Brucella abortus DNA involves TLR9, AIM2, and stimulator of IFN genes (STING). In this study, we observed by microarray analysis that several type I IFN-associated genes, such as IFN-b and guanylate-binding proteins (GBPs), are downreg-ulated in STING knockout (KO) macrophages infected with Brucella or transfected with DNA. Additionally, we determined that STING and cyclic GMP-AMP synthase (cGAS) are important to engage the type I IFN pathway, but only STING is required to induce IL-1b secretion, caspase-1 activation, and GBP2 and GBP3 expression. Furthermore, we determined that STING but not cGAS is critical for host protection against Brucella infection in macrophages and in vivo. This study provides evidence of a cGAS-independent mechanism of STING-mediated protection against an intracellular bacterial infection. Additionally, infected IFN regulatory factor-1 and IFNAR KO macrophages had reduced GBP2 and GBP3 expression and these cells were more permissive to Brucella replication compared with wild-type control macrophages. Because GBPs are critical to target vacuolar bacteria, we determined whether GBP2 and GBPchr3 affect Brucella control in vivo. GBPchr3 but not GBP2 KO mice were more susceptible to bacterial infection, and small interfering RNA treated-macrophages showed reduction in IL-1b secretion and caspase-1 activation. Finally, we also demonstrated that Brucella DNA colocalizes with AIM2, and AIM2 KO mice are less resistant to B. abortus infection. In conclusion, these findings suggest that the STING-dependent type I IFN pathway is critical for the GBP-mediated release of Brucella DNA into the cytosol and subsequent activation of AIM2.

Original languageEnglish (US)
Pages (from-to)607-622
Number of pages16
JournalJournal of Immunology
Volume200
Issue number2
DOIs
StatePublished - Jan 15 2018

ASJC Scopus subject areas

  • Immunology

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    Franco, M. M. C., Marim, F., Guimarães, E. S., Assis, N. R. G., Cerqueira, D. M., Alves-Silva, J., Harms, J., Splitter, G., Smith, J., Kanneganti, T. D., De Queiroz, N. M. G. P., Gutman, D., Barber, G. N., & Oliveira, S. C. (2018). Brucella abortus Triggers a cGAS-Independent STING Pathway to Induce Host Protection That Involves Guanylate-Binding Proteins and Inflammasome Activation. Journal of Immunology, 200(2), 607-622. https://doi.org/10.4049/jimmunol.1700725