Thymidine starvation promotes c-di-AMP-dependent inflammation during pathogenic bacterial infection.
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| Abstract |
Antimicrobials can impact bacterial physiology and host immunity with negative treatment outcomes. Extensive exposure to antifolate antibiotics promotes thymidine-dependent Staphylococcus aureus small colony variants (TD-SCVs), commonly associated with worse clinical outcomes. We show that antibiotic-mediated disruption of thymidine synthesis promotes elevated levels of the bacterial second messenger cyclic di-AMP (c-di-AMP), consequently inducing host STING activation and inflammation. An initial antibiotic screen in Firmicutes revealed that c-di-AMP production was largely driven by antifolate antibiotics targeting dihydrofolate reductase (DHFR), which promotes folate regeneration required for thymidine biosynthesis. Additionally, TD-SCVs exhibited excessive c-di-AMP production and STING activation in a thymidine-dependent manner. Murine lung infection with TD-SCVs revealed STING-dependent elevation of proinflammatory cytokines, causing higher airway neutrophil infiltration and activation compared with normal-colony S. aureus and hemin-dependent SCVs. Collectively, our results suggest that thymidine metabolism disruption in Firmicutes leads to elevated c-di-AMP-mediated STING-dependent inflammation, with potential impacts on antibiotic usage and infection outcomes.
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| Authors | Qing Tang, Mimi R Precit, Maureen K Thomason, Sophie F Blanc, Fariha Ahmed-Qadri, Adelle P McFarland, Daniel J Wolter, Lucas R Hoffman, Joshua J Woodward |
| Journal | Cell host & microbe (Cell Host Microbe) Vol. 30 Issue 7 Pg. 961-974.e6 (07 13 2022) ISSN: 1934-6069 [Electronic] United States |
| PMID | 35439435 (Publication Type: Journal Article) |
| Copyright | Copyright © 2022 Elsevier Inc. All rights reserved. |
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