Characterization of a novel Mycobacterium tuberculosis serine protease Rv1815 in regulating bacterial metabolism and macrophage intracellular survival

 Highlights

• Bacterial serine proteases play a crucial role in the interaction between bacteria and their hosts, facilitating bacterial invasion and contributing to pathogenicity. Mycobacterium tuberculosis possesses multiple serine proteases; however, the mechanisms of action of these proteases remain incompletely understood. In this study, we characterized the role of a novel serine protease, Rv1815, by purifying it in Escherichia coli and creating a rv1815 deletion mutant in M. tuberculosis to investigate its function. Our research revealed that Rv1815 is located in the cytoplasm of macrophages, exhibits serine protease activity, and can be secreted extracellularly. Moreover, we found that rv1815 is essential for bacterial virulence, survival, metabolism, and antibiotic resistance, as demonstrated by proteomic analysis. Rv1815 also influences bacterial morphology, enhances bacterial growth in vitro, and promotes intracellular survival of M. tuberculosis in macrophages. Furthermore, Rv1815 mitigates M. tuberculosis's resistance to rifampicin. This research provides new insights into the relationship between mycobacterial serine proteases and pathogenesis, suggesting that Rv1815 is critical for the physiology and virulence of M. tuberculosis.

Abstract

The serine proteases of Mycobacterium tuberculosis (Mtb) are critical contributors to bacterial invasion and pathogenesis. In this study, we characterized the role of a novel serine protease, the Rv1815 protein, in Mtb by purifying Rv1815 in Escherichia coli and constructing a rv1815 deletion mutant in Mtb. Our findings indicate that Rv1815 exhibits serine protease activity, can be secreted extracellularly, and is localized within the cytoplasm of macrophages. Furthermore, through proteomic analysis, we discovered that rv1815 is essential for the expression of proteins associated with bacterial virulence, survival, metabolism, and antibiotic resistance. Rv1815 promotes intracellular survival of Mtb in macrophages, enhances in vitro bacterial growth, and influences bacterial morphology. Additionally, Rv1815 negatively regulates Mtb's resistance to rifampicin. This study suggests that Rv1815 may play a significant role in the physiology and virulence of Mtb, providing novel insights into the relationship between mycobacterial serine protease and pathogenesis.

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https://www.sciencedirect.com/science/article/pii/S2666517426000441