Journal
CELL HOST & MICROBE
Volume 30, Issue 7, Pages 961-+Publisher
CELL PRESS
DOI: 10.1016/j.chom.2022.03.028
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Funding
- University of Washington Cystic Fibrosis Foundation RDP Fellowship [SINGH15R0]
- Pilot and Feasibility Award from the Cystic Fibrosis Foundation [WOODWA16I0, WOLTER20G0]
- NIH [R01 AI139071, AI16669]
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Antimicrobials can have negative effects on bacterial physiology and host immunity. Antifolate antibiotics can lead to the formation of thymidine-dependent Staphylococcus aureus small colony variants (TD-SCVs), resulting in worse clinical outcomes. Disruption of thymidine synthesis by antibiotics can increase the production of the bacterial second messenger cyclic di-AMP (c-di-AMP), leading to host STING activation and inflammation.
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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