Brucella suppress STING expression via miR-24 to enhance infection.
Brucellosis, 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 infe...
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oai:doaj.org-article:d2b3bfb878264b17877fb7ed40ea63342021-12-02T19:59:43ZBrucella suppress STING expression via miR-24 to enhance infection.1553-73661553-737410.1371/journal.ppat.1009020https://doaj.org/article/d2b3bfb878264b17877fb7ed40ea63342020-10-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009020https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Brucellosis, 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.Mike KhanJerome S HarmsYiping LiuJens EickhoffJin Wen TanTony HuFengwei CaiErika GuimaraesSergio Costa OliveiraRichard DahlYong ChengDelia GutmanGlen N BarberGary A SplitterJudith A SmithPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 16, Iss 10, p e1009020 (2020) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Mike Khan Jerome S Harms Yiping Liu Jens Eickhoff Jin Wen Tan Tony Hu Fengwei Cai Erika Guimaraes Sergio Costa Oliveira Richard Dahl Yong Cheng Delia Gutman Glen N Barber Gary A Splitter Judith A Smith Brucella suppress STING expression via miR-24 to enhance infection. |
| description |
Brucellosis, 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. |
| format |
article |
| author |
Mike Khan Jerome S Harms Yiping Liu Jens Eickhoff Jin Wen Tan Tony Hu Fengwei Cai Erika Guimaraes Sergio Costa Oliveira Richard Dahl Yong Cheng Delia Gutman Glen N Barber Gary A Splitter Judith A Smith |
| author_facet |
Mike Khan Jerome S Harms Yiping Liu Jens Eickhoff Jin Wen Tan Tony Hu Fengwei Cai Erika Guimaraes Sergio Costa Oliveira Richard Dahl Yong Cheng Delia Gutman Glen N Barber Gary A Splitter Judith A Smith |
| author_sort |
Mike Khan |
| title |
Brucella suppress STING expression via miR-24 to enhance infection. |
| title_short |
Brucella suppress STING expression via miR-24 to enhance infection. |
| title_full |
Brucella suppress STING expression via miR-24 to enhance infection. |
| title_fullStr |
Brucella suppress STING expression via miR-24 to enhance infection. |
| title_full_unstemmed |
Brucella suppress STING expression via miR-24 to enhance infection. |
| title_sort |
brucella suppress sting expression via mir-24 to enhance infection. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2020 |
| url |
https://doaj.org/article/d2b3bfb878264b17877fb7ed40ea6334 |
| work_keys_str_mv |
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