Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNA
Abstract The immunologic consequences of using bactericidal versus bacteriostatic antibiotic treatments are unclear. We observed a bacteriostatic (growth halting) treatment was more protective than a bactericidal (bacteria killing) treatment in a murine peritonitis model. To understand this unexpect...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54497-3 |
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| author | Julia L. Gross Rahul Basu Clinton J. Bradfield Jing Sun Sinu P. John Sanchita Das John P. Dekker David S. Weiss Iain D. C. Fraser |
| author_facet | Julia L. Gross Rahul Basu Clinton J. Bradfield Jing Sun Sinu P. John Sanchita Das John P. Dekker David S. Weiss Iain D. C. Fraser |
| author_sort | Julia L. Gross |
| collection | DOAJ |
| description | Abstract The immunologic consequences of using bactericidal versus bacteriostatic antibiotic treatments are unclear. We observed a bacteriostatic (growth halting) treatment was more protective than a bactericidal (bacteria killing) treatment in a murine peritonitis model. To understand this unexpected difference, we compared macrophage responses to bactericidal treated bacteria or bacteriostatic treated bacteria. We found that Gram-negative bacteria treated with bactericidal drugs induced more proinflammatory cytokines than those treated with bacteriostatic agents. Bacterial DNA – released only by bactericidal treatments – exacerbated inflammatory signaling through TLR9. Without TLR9 signaling, the in vivo efficacy of bactericidal drug treatment was rescued. This demonstrates that antibiotics can act in important ways distinct from bacterial inhibition: like causing treatment failure by releasing DNA that induces excessive inflammation. These data establish a novel link between how an antibiotic affects bacterial physiology and subsequent immune system engagement, which may be relevant for optimizing treatments to simultaneously clear bacteria and modulate inflammation. |
| format | Article |
| id | doaj-art-5cf8fa006a8a40e3b86d8ef3c745661e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5cf8fa006a8a40e3b86d8ef3c745661e2024-12-01T12:34:37ZengNature PortfolioNature Communications2041-17232024-11-0115111610.1038/s41467-024-54497-3Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNAJulia L. Gross0Rahul Basu1Clinton J. Bradfield2Jing Sun3Sinu P. John4Sanchita Das5John P. Dekker6David S. Weiss7Iain D. C. Fraser8Emory University/NIAID Graduate Partnership ProgramSignaling Systems Section, Laboratory of Immune System Biology, NIAIDSignaling Systems Section, Laboratory of Immune System Biology, NIAIDSignaling Systems Section, Laboratory of Immune System Biology, NIAIDSignaling Systems Section, Laboratory of Immune System Biology, NIAIDDepartment of Laboratory Medicine, NIH Clinical Center, NIHDepartment of Laboratory Medicine, NIH Clinical Center, NIHDivision of Infectious Diseases, Emory University School of MedicineSignaling Systems Section, Laboratory of Immune System Biology, NIAIDAbstract The immunologic consequences of using bactericidal versus bacteriostatic antibiotic treatments are unclear. We observed a bacteriostatic (growth halting) treatment was more protective than a bactericidal (bacteria killing) treatment in a murine peritonitis model. To understand this unexpected difference, we compared macrophage responses to bactericidal treated bacteria or bacteriostatic treated bacteria. We found that Gram-negative bacteria treated with bactericidal drugs induced more proinflammatory cytokines than those treated with bacteriostatic agents. Bacterial DNA – released only by bactericidal treatments – exacerbated inflammatory signaling through TLR9. Without TLR9 signaling, the in vivo efficacy of bactericidal drug treatment was rescued. This demonstrates that antibiotics can act in important ways distinct from bacterial inhibition: like causing treatment failure by releasing DNA that induces excessive inflammation. These data establish a novel link between how an antibiotic affects bacterial physiology and subsequent immune system engagement, which may be relevant for optimizing treatments to simultaneously clear bacteria and modulate inflammation.https://doi.org/10.1038/s41467-024-54497-3 |
| spellingShingle | Julia L. Gross Rahul Basu Clinton J. Bradfield Jing Sun Sinu P. John Sanchita Das John P. Dekker David S. Weiss Iain D. C. Fraser Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNA Nature Communications |
| title | Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNA |
| title_full | Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNA |
| title_fullStr | Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNA |
| title_full_unstemmed | Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNA |
| title_short | Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNA |
| title_sort | bactericidal antibiotic treatment induces damaging inflammation via tlr9 sensing of bacterial dna |
| url | https://doi.org/10.1038/s41467-024-54497-3 |
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