Mycobacterium tuberculosis short mutant H37Rv-S with reduced growth adaptability is more readily recognized by the host immune system.

Mycobacterium tuberculosis (Mtb) is the bacterium responsible for causing Tuberculosis (TB) and understanding its mechanisms of virulence, persistence, and pathogenesis is a global research priority. Attenuated strains of Mtb are valuable tools for investigating the genes and proteins involved in these processes. In this study, we identified an Mtb mutant, H37Rv-S, which exhibits a shorter mycelium, smoother colony, slower growth, and reduced antibiotics resistance compared to the wild-type strain H37Rv. Genomic sequencing revealed 34 mutation events in the coding regions of H37Rv-S, affecting 31 genes. We conducted TMT-labeling quantitative proteomics to compare the expression differences between H37Rv-S and H37Rv, as well as their infected bone marrow derived macrophages (BMDMs). The results showed that 716 protein groups (23.96 %) in H37Rv-S and 115 protein groups (2.99 %) in the infected BMDMs were differentially expressed. The dysregulated proteins in H37Rv-S correspond with its phenotype characteristics. Among the 31 affected genes in H37Rv-S, 10 showed upregulation and 1 showed downregulation at the protein level. Notable, 16 associated network proteins in the phoP/phoR system were significantly dysregulated due to a frameshift mutation in phoP, altering its protein sequence after Phe45. The dysregulated host proteins in H37Rv-S were associated with immune response, necroptosis, and ferroptosis. Additionally, H37Rv-S demonstrated reduced survival capability in strain fluorescence labeling and colony-forming unit (CFU) counting post-infection of BMDM cells. These findings suggest that H37Rv-S is an attenuated strain exhibiting defective phenotype characteristics and is more readily recognized and eliminated by the host. This enhanced understanding of the differences between virulent and attenuated strains could facilitate the development of new targets and therapeutics for TB prevention and treatment.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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