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A guardian role of TagA in protecting Mycobacterium tuberculosis from nitrosative killing

ABSTRACT: Upon activation, macrophages generate substantial levels of reactive nitrogen species (RNS), which can induce alkylating damage in the DNA of intracellular Mycobacterium tuberculosis (Mtb) and thereby restrict bacterial replication. However, the molecular mechanisms by which Mtb repairs such DNA lesions remain poorly understood. Here, we identified genes required for Mtb survival in distinct macrophage subsets using transposon insertion sequencing (Tn-seq). Among these, tagA displayed a specialized role in Mtb survival in M1-polarized macrophages, as well as in mice at 4 weeks post-infection, a stage when macrophages are biased toward an M1-polarized state. Mechanistically, TagA conferred resistance to the DNA alkylating agent methyl methanesulfonate (MMS) through its 3-methyladenine (3-MA) excision activity, and substrate binding in Mtb depended on the conserved catalytic residue Glu48. Critically, TagA was found to inhibit the alkylated damage to Mtb genome from nitrosative stress characteristic of M1 polarized macrophages. Furthermore, pharmacological inhibition of iNOS with S-methylisothiourea sulfate (SMT) in mice or genetic deletion of nos2a in zebrafish markedly rescued the survival defect of ΔtagA, further supporting that this phenotype is primarily driven by host nitrosative stress. Together, these findings reveal a previously unappreciated mechanism by which the DNA repair enzyme TagA protects Mtb against 3-MA DNA damage under nitrosative stress, thereby promoting bacterial survival in M1-polarized macrophages and during in vivo infection.

ORGANISM(S): Mycobacterium tuberculosis

PROVIDER: GSE334642 | GEO | 2026/07/08

REPOSITORIES: GEO

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