TY - JOUR
T1 - Brucella abortus Triggers a cGAS-Independent STING Pathway to Induce Host Protection That Involves Guanylate-Binding Proteins and Inflammasome Activation
AU - Franco, Miriam M.Costa
AU - Marim, Fernanda
AU - Guimarães, Erika S.
AU - Assis, Natan R.G.
AU - Cerqueira, Daiane M.
AU - Alves-Silva, Juliana
AU - Harms, Jerome
AU - Splitter, Gary
AU - Smith, Judith
AU - Kanneganti, Thirumala Devi
AU - De Queiroz, Nina M.G.P.
AU - Gutman, Delia
AU - Barber, Glen N.
AU - Oliveira, Sergio C.
N1 - Funding Information:
This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico Grants 464711/2014-2, 402527/2013-5, 443662/2014-2, and 302660/ 2015-1, Fundac¸ão de Amparo a Pesquisa do Estado de Minas Gerais Grant APQ 837/15 and Rede Mineira de Imunobiologicos Grant 00140-16, as well as by Coor-denac¸ão de Aperfeic¸oamento de Pessoal de Nível Superior Grant 030448/2013-1 and National Institutes of Health Grant R01 AI116453.
Publisher Copyright:
Copyright © 2018 by The American Association of Immunologists, Inc.
PY - 2018/1/15
Y1 - 2018/1/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85044734407&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044734407&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1700725
DO - 10.4049/jimmunol.1700725
M3 - Article
C2 - 29203515
AN - SCOPUS:85044734407
VL - 200
SP - 607
EP - 622
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 2
ER -