| First Author | Tang Q | Year | 2022 |
| Journal | Cell Host Microbe | Volume | 30 |
| Issue | 7 | Pages | 961-974.e6 |
| PubMed ID | 35439435 | Mgi Jnum | J:328696 |
| Mgi Id | MGI:7316237 | Doi | 10.1016/j.chom.2022.03.028 |
| Citation | Tang Q, et al. (2022) Thymidine starvation promotes c-di-AMP-dependent inflammation during pathogenic bacterial infection. Cell Host Microbe 30(7):961-974.e6 |
| abstractText | 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. |
