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Pathogenesis of S. aureus thymidine-dependent small-colony variants

Award Number: R15AI190949
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Pathogenesis of S. aureus thymidine-dependent small-colony variants - Project Summary/Abstract Staphylococcus aureus thymidine-dependent small-colony variants (TD-SCVs) are frequently isolated from the airways of cystic fibrosis (CF) patients. These mutants are thymidine auxotrophic, resulting from inactivating mutations in thymidylate synthase (ThyA) caused by extensive use of anti-folate antibiotics. These mutants have distinct metabolism and enlarged cell sizes. Moreover, colonization of TD-SCVs is associated with chronic infection and more severe pulmonary decline, while the mechanism remains to be fully elucidated. The infection outcome is determined by both the bacterial burden and the host inflammation induced by these bacteria. Our long-term goal is to reveal the mechanisms by which TD-SCV induces more severe lung outcomes and to provide insights for innovative therapy. The central hypothesis of this proposal is that the alternation in metabolism and cell wall composition of S. aureus TD-SCV affects its survival and infection outcomes. The research in this proposal pursues two specific aims: (1) CF neutrophils are glutamine-deficient, making de novo glutamine synthesis in TD-SCV crucial for its intracellular survival after phagocytosis. Our data indicate that the transcription of glutamine synthesis genes in S. aureus is regulated by the transcriptional repressor GlnR, whose DNA-binding ability is modulated by both glutamine synthetase (GlnA) and the PII family signaling protein PstA. PstA undergoes conformational changes upon binding to its ligand, c-di-AMP, whose production changes in response to intracellular glutamine levels. We will characterize a previously unrecognized glutamine feedback regulatory circuit in which glutamine modulates GlnR activity by altering c-di-AMP levels, which in turn regulate the interaction dynamics of GlnR, PstA, and GlnA, ultimately impacting the growth of TD-SCV. (2) Our data indicate that S. aureus TD-SCV infection leads to enhanced production of the inflammatory cytokine CCL3 and subsequent elevated neutrophil infiltration. Furthermore, the elevated CCL3 induction is likely attributed to the distinct cell wall structure of TD-SCV. We will characterize how thymidine influences the synthesis of cell wall components in TD-SCV and explore its correlation with increased CCL3 induction. Additionally, we will investigate the contribution of elevated CCL3 to lung damage in a murine lung infection model. Our study will provide a potential mechanistic explanation for the persistent survival of TD- SCV in the airway and the associated decline in lung function among people with CF.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $533,850 )
2026	2026	UNIVERSITY OF TEXAS AT ARLINGTON	701 S NEDDERMAN DR	ARLINGTON	TX	76019	TARRANT	USA	Allergy and Infectious Diseases Research	000	1	3/27/2026	NEW	$533,850
														Subtotal = $533,850

Grand Total All Awards = $533,850

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Pathogenesis of S. aureus thymidine-dependent small-colony variants

Award Number: R15AI190949

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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