RGD Reference Report - Brucella abortus Triggers a cGAS-Independent STING Pathway To Induce Host Protection That Involves Guanylate-Binding Proteins and Inflammasome Activation. - Rat Genome Database

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

Authors: Costa Franco, Miriam M  Marim, Fernanda  Guimarães, Erika S  Assis, Natan R G  Cerqueira, Daiane M  Alves-Silva, Juliana  Harms, Jerome  Splitter, Gary  Smith, Judith  Kanneganti, Thirumala-Devi  de Queiroz, Nina M G P  Gutman, Delia  Barber, Glen N  Oliveira, Sergio C 
Citation: Costa Franco MM, etal., J Immunol. 2018 Jan 15;200(2):607-622. doi: 10.4049/jimmunol.1700725. Epub 2017 Dec 4.
RGD ID: 39128199
Pubmed: PMID:29203515   (View Abstract at PubMed)
PMCID: PMC5760291   (View Article at PubMed Central)
DOI: DOI:10.4049/jimmunol.1700725   (Journal Full-text)

Immunity against microbes depends on recognition of pathogen-associated molecular patterns by innate 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-β and guanylate-binding proteins (GBPs), are downregulated 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-1β 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-1β 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
STING1Humanbrucellosis  ISOSting1 (Mus musculus) RGD 
Sting1Ratbrucellosis  ISOSting1 (Mus musculus) RGD 
Sting1Mousebrucellosis  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Sting1  (stimulator of interferon response cGAMP interactor 1)

Genes (Mus musculus)
Sting1  (stimulator of interferon response cGAMP interactor 1)

Genes (Homo sapiens)
STING1  (stimulator of interferon response cGAMP interactor 1)


Additional Information