OMP38 of Carbapenem‐Resistant Acinetobacter Baumannii‐Mediated mtDNA Release Activates the cGAS‐STING Signaling to Induce Inflammatory Response
Abstract Carbapenem‐resistant Acinetobacter baumannii (CRAB) has become a major threat in the treatment of bacterial infection, and immunotherapy in a non‐antibiotic‐dependent manner is an effective way to overcome CRAB infection. However, the role of the innate immune response in CRAB infection is...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202408292 |
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| author | Yang Yang Yuanyuan Zeng Jianjie Zhu Jianjun Li Lei Gu Lin Wei Zeyi Liu Jian‐an Huang |
| author_facet | Yang Yang Yuanyuan Zeng Jianjie Zhu Jianjun Li Lei Gu Lin Wei Zeyi Liu Jian‐an Huang |
| author_sort | Yang Yang |
| collection | DOAJ |
| description | Abstract Carbapenem‐resistant Acinetobacter baumannii (CRAB) has become a major threat in the treatment of bacterial infection, and immunotherapy in a non‐antibiotic‐dependent manner is an effective way to overcome CRAB infection. However, the role of the innate immune response in CRAB infection is poorly understood. Here, it is reported that CRAB infection induced a cytosolic DNA‐sensing signaling pathway and significant IFN‐β production in mice post‐CRAB infection. The knockout of STING reduced bacterial burden, the production of inflammatory cytokines, and lung injury in mice post CRAB infection. The cytosolic DNA sensor cyclic GMP‐AMP synthase (cGAS) and the adaptor protein stimulator of interferon genes (STING) are required for CRAB‐induced IFN‐β expression in macrophages. Intriguingly, CRAB utilized outer membrane vesicles (OMVs) to transport outer membrane protein 38 (OMP38) into mitochondria, triggering mitochondrial DNA (mtDNA) release into the cytosol through the mitochondrial permeability transition pore (mPTP) and activating the cGAS‐STING signaling. Finally, epigallocatechin gallate (EGCG) is demonstrated to block the activation of the cGAS‐STING pathway and ameliorate CRAB‐induced excessive inflammatory response. These results demonstrated that the early innate immune response to CRAB infection is activated in a cGAS‐STING‐dependent manner, which could be a potential therapeutic target for CRAB infection. |
| format | Article |
| id | doaj-art-8935c5d08ef84987abb7941eb536ad6f |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-8935c5d08ef84987abb7941eb536ad6f2025-01-29T09:50:19ZengWileyAdvanced Science2198-38442025-01-01124n/an/a10.1002/advs.202408292OMP38 of Carbapenem‐Resistant Acinetobacter Baumannii‐Mediated mtDNA Release Activates the cGAS‐STING Signaling to Induce Inflammatory ResponseYang Yang0Yuanyuan Zeng1Jianjie Zhu2Jianjun Li3Lei Gu4Lin Wei5Zeyi Liu6Jian‐an Huang7Department of Pulmonary and Critical Care Medicine the First Affiliated Hospital of Soochow University Suzhou 215006 ChinaDepartment of Pulmonary and Critical Care Medicine the First Affiliated Hospital of Soochow University Suzhou 215006 ChinaDepartment of Pulmonary and Critical Care Medicine the First Affiliated Hospital of Soochow University Suzhou 215006 ChinaDepartment of Pulmonary and Critical Care Medicine the First Affiliated Hospital of Soochow University Suzhou 215006 ChinaDepartment of Pulmonary and Critical Care Medicine the First Affiliated Hospital of Soochow University Suzhou 215006 ChinaDepartment of Infectious Diseases The First Affiliated Hospital of Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pulmonary and Critical Care Medicine the First Affiliated Hospital of Soochow University Suzhou 215006 ChinaDepartment of Pulmonary and Critical Care Medicine the First Affiliated Hospital of Soochow University Suzhou 215006 ChinaAbstract Carbapenem‐resistant Acinetobacter baumannii (CRAB) has become a major threat in the treatment of bacterial infection, and immunotherapy in a non‐antibiotic‐dependent manner is an effective way to overcome CRAB infection. However, the role of the innate immune response in CRAB infection is poorly understood. Here, it is reported that CRAB infection induced a cytosolic DNA‐sensing signaling pathway and significant IFN‐β production in mice post‐CRAB infection. The knockout of STING reduced bacterial burden, the production of inflammatory cytokines, and lung injury in mice post CRAB infection. The cytosolic DNA sensor cyclic GMP‐AMP synthase (cGAS) and the adaptor protein stimulator of interferon genes (STING) are required for CRAB‐induced IFN‐β expression in macrophages. Intriguingly, CRAB utilized outer membrane vesicles (OMVs) to transport outer membrane protein 38 (OMP38) into mitochondria, triggering mitochondrial DNA (mtDNA) release into the cytosol through the mitochondrial permeability transition pore (mPTP) and activating the cGAS‐STING signaling. Finally, epigallocatechin gallate (EGCG) is demonstrated to block the activation of the cGAS‐STING pathway and ameliorate CRAB‐induced excessive inflammatory response. These results demonstrated that the early innate immune response to CRAB infection is activated in a cGAS‐STING‐dependent manner, which could be a potential therapeutic target for CRAB infection.https://doi.org/10.1002/advs.202408292Acinetobacter baumanniicarbapenem‐resistantcGAS‐STINGmitochondrial DNAouter membrane protein 38 |
| spellingShingle | Yang Yang Yuanyuan Zeng Jianjie Zhu Jianjun Li Lei Gu Lin Wei Zeyi Liu Jian‐an Huang OMP38 of Carbapenem‐Resistant Acinetobacter Baumannii‐Mediated mtDNA Release Activates the cGAS‐STING Signaling to Induce Inflammatory Response Advanced Science Acinetobacter baumannii carbapenem‐resistant cGAS‐STING mitochondrial DNA outer membrane protein 38 |
| title | OMP38 of Carbapenem‐Resistant Acinetobacter Baumannii‐Mediated mtDNA Release Activates the cGAS‐STING Signaling to Induce Inflammatory Response |
| title_full | OMP38 of Carbapenem‐Resistant Acinetobacter Baumannii‐Mediated mtDNA Release Activates the cGAS‐STING Signaling to Induce Inflammatory Response |
| title_fullStr | OMP38 of Carbapenem‐Resistant Acinetobacter Baumannii‐Mediated mtDNA Release Activates the cGAS‐STING Signaling to Induce Inflammatory Response |
| title_full_unstemmed | OMP38 of Carbapenem‐Resistant Acinetobacter Baumannii‐Mediated mtDNA Release Activates the cGAS‐STING Signaling to Induce Inflammatory Response |
| title_short | OMP38 of Carbapenem‐Resistant Acinetobacter Baumannii‐Mediated mtDNA Release Activates the cGAS‐STING Signaling to Induce Inflammatory Response |
| title_sort | omp38 of carbapenem resistant acinetobacter baumannii mediated mtdna release activates the cgas sting signaling to induce inflammatory response |
| topic | Acinetobacter baumannii carbapenem‐resistant cGAS‐STING mitochondrial DNA outer membrane protein 38 |
| url | https://doi.org/10.1002/advs.202408292 |
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