PT - JOURNAL ARTICLE AU - Qing Tang AU - Mimi R. Precit AU - Maureen K. Thomason AU - Fariha Ahmed-Qadri AU - Adelle P. McFarland AU - Daniel J. Wolter AU - Lucas R. Hoffman AU - Joshua J. Woodward TI - Thymidine starvation promotes c-di-AMP dependent inflammation during infection AID - 10.1101/2020.08.21.261750 DP - 2021 Jan 01 TA - bioRxiv PG - 2020.08.21.261750 4099 - http://biorxiv.org/content/early/2021/09/14/2020.08.21.261750.short 4100 - http://biorxiv.org/content/early/2021/09/14/2020.08.21.261750.full AB - Antibiotics remain one of the most effective methods for controlling bacterial infection. However, the diverse impacts of antimicrobials on bacterial physiology and host immunity remain unclear. A comprehensive antibiotic screen revealed that disruption of thymidine synthesis in Firmicutes with anti-folate antibiotics promoted elevated levels of the bacterial second messenger cyclic di-AMP, and consequently induced host STING activation during infection. Extensive exposure to antibiotics targeting folate synthesis drives the emergence of thymidine-dependent Staphylococcus aureus SCVs (TD-SCVs). Respiratory infections with TD-SCVs are common among children with cystic fibrosis and are associated with worse clinical outcomes, although the underlying pathophysiological mechanisms remain to be defined. Our study reveals that TD-SCV isolates 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, leading to higher airway neutrophil infiltration and activation comparing to normal colony S. aureus and hemin-dependent SCV. Our results suggest the elevated inflammatory capacity of TD-SCVs contribute to their pathogenesis and revealed a new aspect of STING signaling in the airway by characterizing its role in neutrophil recruitment.Competing Interest StatementThe authors have declared no competing interest.