Ongoing evolution of PE/PPE genes in Mycobacterium tuberculosis associated with drug resistance and host immune response

Abstract

Tuberculosis remains a significant global health challenge, partly due to Mycobacterium tuberculosis (Mtb)’s remarkable evolutionary adaptation to antibiotics and human immune responses. Around 10% of its genome comprises PE/PPE genes, whose functions and evolutionary dynamics are poorly understood due to their repetitive sequences and high GC content. In this study, we analyzed 51,229 global Mtb genomes using an advanced genome-masking method, revealing numerous PE/PPE genes under positive selection, potentially facilitating antibiotic resistance and immune evasion. Notably, PPE51 often loses its function in strains resistant to multiple antibiotics, suggesting a role in bacterial survival during drug treatment. Additionally, we identified mutation-prone regions within six PE/PPE genes, highlighting potential targets for future vaccine development. Collectively, our findings underscore the crucial role of PE/PPE genes in Mtb evolution and drug resistance, providing valuable insights to inform novel therapeutic and vaccine strategies.