Brucella suppress STING expression via miR-24 to enhance infection

dc.contributor.authorKhan, Mike
dc.contributor.authorHarms, Jerome S.
dc.contributor.authorLiu, Yiping
dc.contributor.authorEickhoff, Jens
dc.contributor.authorTan, Jin Wen
dc.contributor.authorHu, Tony
dc.contributor.authorCai, Fengwei
dc.contributor.authorGuimaraes, Erika
dc.contributor.authorOliveira, Sergio Costa
dc.contributor.authorDahl, Richard
dc.contributor.authorCheng, Yong
dc.contributor.authorGutman, Delia
dc.contributor.authorBarber, Glen N.
dc.contributor.authorSplitter, Gary A.
dc.contributor.authorSmith, Judith A.
dc.contributor.departmentMicrobiology and Immunology, School of Medicineen_US
dc.date.accessioned2021-11-10T21:27:36Z
dc.date.available2021-11-10T21:27:36Z
dc.date.issued2020-10-27
dc.description.abstractBrucellosis, caused by a number of Brucella species, remains the most prevalent zoonotic disease worldwide. Brucella establish chronic infections within host macrophages despite triggering cytosolic innate immune sensors, including Stimulator of Interferon Genes (STING), which potentially limit infection. In this study, STING was required for control of chronic Brucella infection in vivo. However, early during infection, Brucella down-regulated STING mRNA and protein. Down-regulation occurred post-transcriptionally, required live bacteria, the Brucella type IV secretion system, and was independent of host IRE1-RNase activity. STING suppression occurred in MyD88-/- macrophages and was not induced by Toll-like receptor agonists or purified Brucella lipopolysaccharide (LPS). Rather, Brucella induced a STING-targeting microRNA, miR-24-2, in a type IV secretion system-dependent manner. Furthermore, STING downregulation was inhibited by miR-24 anti-miRs and in Mirn23a locus-deficient macrophages. Failure to suppress STING expression in Mirn23a-/- macrophages correlated with diminished Brucella replication, and was rescued by exogenous miR-24. Mirn23a-/- mice were also more resistant to splenic colonization one week post infection. Anti-miR-24 potently suppressed replication in wild type, but much less in STING-/- macrophages, suggesting most of the impact of miR-24 induction on replication occurred via STING suppression. In summary, Brucella sabotages cytosolic surveillance by miR-24-dependent suppression of STING expression; post-STING activation “damage control” via targeted STING destruction may enable establishment of chronic infection., Cytosolic pattern recognition receptors, such as the nucleotide-activated STING molecule, play a critical role in the innate immune system by detecting the presence of intracellular invaders. Brucella bacterial species establish chronic infections in macrophages despite initially activating STING. STING participates in the control of Brucella infection, as mice or cells lacking STING show a higher burden of Brucella infection. However, we have found that early following infection, Brucella upregulates a microRNA, miR-24, that targets the STING messenger RNA, resulting in lower STING levels. Dead bacteria or bacteria lacking a functional type IV secretion system were defective at upregulating miR-24 and STING suppression, suggesting an active bacteria-driven process. Failure to upregulate miR-24 and suppress STING greatly compromised the capacity of Brucella to replicate inside macrophages and in mice. Thus, although Brucella initially activate STING during infection, the ensuing STING downregulation serves as a “damage control” mechanism, enabling intracellular infection. Viruses have long been known to target immune sensors such as STING. Our results indicate that intracellular bacterial pathogens also directly target innate immune receptors to enhance their infectious success.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationKhan, M., Harms, J. S., Liu, Y., Eickhoff, J., Tan, J. W., Hu, T., Cai, F., Guimaraes, E., Oliveira, S. C., Dahl, R., Cheng, Y., Gutman, D., Barber, G. N., Splitter, G. A., & Smith, J. A. (2020). Brucella suppress STING expression via miR-24 to enhance infection. PLoS Pathogens, 16(10), e1009020. https://doi.org/10.1371/journal.ppat.1009020en_US
dc.identifier.issn1553-7366en_US
dc.identifier.urihttps://hdl.handle.net/1805/26971
dc.language.isoenen_US
dc.publisherPloSen_US
dc.relation.isversionof10.1371/journal.ppat.1009020en_US
dc.relation.journalPLoS Pathogensen_US
dc.rightsAttribution 4.0 United States
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.sourcePublisheren_US
dc.subjectStimulator of Interferon Genes (STING)en_US
dc.subjectBrucellosisen_US
dc.subjectmiR-24en_US
dc.titleBrucella suppress STING expression via miR-24 to enhance infectionen_US
dc.typeArticleen_US
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