MyD88 and STING Signaling Pathways Are Required for IRF3-Mediated IFN-β Induction in Response to Brucella abortus Infection

• Published in: PloS one Vol. 6; no. 8; p. e23135
• Main Authors: de Almeida, Leonardo A., Carvalho, Natalia B., Oliveira, Fernanda S., Lacerda, Thais L. S., Vasconcelos, Anilton C., Nogueira, Lucas, Bafica, Andre, Silva, Aristóbolo M., Oliveira, Sergio C.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2011; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; Bacillus anthracis; Bacteria; Bacterial diseases; Bacterial infections; Biochemistry; Biology; Brucella; Brucella abortus; Brucella abortus - genetics; Brucella abortus - isolation & purification; Brucellosis - metabolism; Brucellosis - microbiology; Cell Line; Cytokines; Deoxyribonucleic acid; DNA; DNA, Bacterial - genetics; DNA-directed RNA polymerase; Domestic animals; Endoplasmic reticulum; Fever; Gene expression; Gram-negative bacteria; Immune response; Immune system; Immunology; Infections; Interferon; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - physiology; Interferon-beta - biosynthesis; Intracellular signalling; Kinases; Listeria; Listeria monocytogenes; Macrophages; Macrophages - metabolism; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; Parasitology; Pathogens; Phenotypes; Phosphorylation; Proteins; Ribonucleic acid; RNA; RNA polymerase; RNA Polymerase III - metabolism; Signal transduction; Spleen; Spleen - cytology; Spleen - metabolism; Splenocytes; Stat1 protein; STAT1 Transcription Factor - metabolism; TNF-Related Apoptosis-Inducing Ligand - metabolism; Tuberculosis; Tumor necrosis factor-TNF; Viruses; β-Interferon; γ-Interferon; Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023135

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.