title: MyD88 and STING signaling pathways are required for IRF3-mediated IFN-β induction in response to Brucella abortus infection.
abstract: Type I interferons (IFNs) are cytokines that orchestrate diverse immune responses to viral and bacterial infections. Although typically considered to be most important molecules in response to viruses, type I IFNs are also induced by most, if not all, bacterial pathogens. In this study, we addressed the role of type I IFN signaling during Brucella abortus infection, a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. Herein, we have shown that B. abortus induced IFN-β in macrophages and splenocytes. Further, IFN-β induction by Brucella was mediated by IRF3 signaling pathway and activates IFN-stimulated genes via STAT1 phosphorylation. In addition, IFN-β expression induced by Brucella is independent of TLRs and TRIF signaling but MyD88-dependent, a pathway not yet described for Gram-negative bacteria. Furthermore, we have identified Brucella DNA as the major bacterial component to induce IFN-β and our study revealed that this molecule operates through a mechanism dependent on RNA polymerase III to be sensed probably by an unknown receptor via the adaptor molecule STING. Finally, we have demonstrated that IFN-αβR KO mice are more resistant to infection suggesting that type I IFN signaling is detrimental to host control of Brucella. This resistance phenotype is accompanied by increased IFN-γ and NO production by IFN-αβR KO spleen cells and reduced apoptosis.
authors.affiliation: Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte-Minas Gerais, Brazil.
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: de Almeida
authors.forename: Natalia B
authors.initials: NB
authors.lastname: Carvalho
authors.forename: Fernanda S
authors.initials: FS
authors.lastname: Oliveira
authors.forename: Thais L S
authors.initials: TL
authors.lastname: Lacerda
authors.forename: Anilton C
authors.initials: AC
authors.lastname: Vasconcelos
authors.forename: Lucas
authors.initials: L
authors.lastname: Nogueira
authors.forename: Andre
authors.initials: A
authors.lastname: Bafica
authors.forename: Aristóbolo M
authors.initials: AM
authors.lastname: Silva
authors.forename: Sergio C
authors.initials: SC
authors.lastname: Oliveira
mesh_terms: D000818:Animals; D002003:Brucella abortus / Q000235:genetics / Q000302:isolation & purification*; D002006:Brucellosis / Q000378:metabolism* / Q000382:microbiology; D002460:Cell Line; D004269:DNA, Bacterial / Q000235:genetics; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D016899:Interferon-beta / Q000096:biosynthesis*; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D010766:Phosphorylation; D012320:RNA Polymerase III / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D000099197:STING Protein
chemical_list: D004269:DNA, Bacterial; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D012320:RNA Polymerase III; D050794:STAT1 Transcription Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C494233:Irf3 protein, mouse; C507780:Myd88 protein, mouse; C494080:Stat1 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C505654:Tnfsf10 protein, mouse