# NIH grant: Bacterial modulation of host metabolism and immunity during infection (1R01AI198349-01) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R01AI198349-01)

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NIH grant 1R01AI198349-01: Bacterial modulation of host metabolism and immunity during infection
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Qing  Tang. Award: $583822.
Start: 2026-06-25T00:00:00.
Project Summary/Abstract
Anti-folate antibiotics treat various bacterial infections by inhibiting de novo pyrimidine synthesis through
thymidylate synthase (ThyA) inactivation, leading to bacterial thymineless death (TLD). Despite extensive
research, TLD mechanisms remain unclear. Pathogens may evade TLD by salvaging host nucleotides, but this
process is poorly understood due to lack of suitable experimental models. These knowledge gaps limit our
understanding of antimicrobial resistance and hinder development of optimized therapies for drug-resistant
bacteria.
 Anti-folates commonly treat meningitis and refractory listeriosis caused by drug-resistant Listeria
monocytogenes (Lm). As a facultative intracellular pathogen, Lm serves as an ideal model for studying TLD
during both extracellular and intracellular growth. Using a thymidine auxotroph of Lm (ΔthyA) as a model, we
have begun uncovering how bacteria evade TLD by altering their physiology, modulating host metabolic pools,
and salvaging host nucleotides. This proposal will investigate mechanisms underlying each pathway: (1) Cyclic
di-AMP (c-di-AMP), a bacterial second messenger regulating stress responses, is significantly elevated in ΔthyA.
Elevated c-di-AMP inhibits TLD by binding to and inhibiting PII family protein PstA. This study will identify
downstream PstA targets and characterize how its interaction with c-di-AMP inhibits TLD. (2) C-di-AMP
ptoducecd by Lm activates host immune adaptor protein STING, leading to interferon-β (IFN-β) production, which
triggers host nucleotide salvage gene expression and thymidine accumulation. This study will investigate our
hypothesis that IFN-β-dependent thymidine accumulation supports bacterial survival. (3) Beyond stimulating host
thymidine synthesis via c-di-AMP, we identified Lm surface nucleotidase CsnuC, which enables Lm to convert
host nucleic acids and uptake-inaccessible nucleotides into thymidine. We will characterize how CsnuC salvages
various pyrimidine sources during infection.
 Our investigation of these three TLD suppression pathways will deepen our understanding of bacterial
interactions with host metabolic and immune systems, influencing pathogen survival and infection outcomes.
These novel mechanisms may serve as therapeutic targets for treating drug-resistant bacterial infections.
```



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