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NagA deletion of Mycobacterium tuberculosis leads to a defective cell wall integrity and invokes unique host signatures rendering the pathogen attenuated in guinea pigs.

ABSTRACT: Mtb N-acetylglucosamine-6-phosphate deacetylase (NagA, Rv3332) belonging to the amido-hydrolase superfamily catalyzes a reaction which generates vital amino-sugars required as precursors for Mtb cell wall biosynthesis or glycolysis. In this study, a nagA gene deletion mutant of Mtb was generated, which showed an altered cellular morphology and cell wall structure. In vitro experiments revealed the importance of NagA under lysosomal, hypoxic and antibiotic stress and in biofilm formation. MtbΔnagA mutant showed reduced bacillary count inside macrophages in comparison to the parental strain. Deletion of nagA rendered the pathogen attenuated in guinea pigs exhibiting significantly lower bacillary counts as well as much reduced pathological damage in infected tissues in comparison to the wild type strain. Moreover, guinea pigs infected with MtbΔnagA mutant showed cent percent survival rate. Further, RNA sequencing analysis of the lung tissues from infected guinea pigs revealed that MtbΔnagA infection led to significantly lesser changes in gene expression in the host compared to the uninfected control while inducing a stronger immune response. In contrast, the virulent Mtb strain drastically altered the host transcriptome favouring its survival. To conclude, our study demonstrated the importance of NagA in M. tuberculosis pathogenicity establishing it as a potential anti-tubercular target. Further, we consider MtbΔnagA to have potential to be explored as a TB vaccine candidate.

ORGANISM(S): Cavia porcellus

PROVIDER: GSE275579 | GEO | 2025/08/02

REPOSITORIES: GEO

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