The ppsA-ppsE gene cluster in Mycobacterium bovis: structure, function, and role in virulence

Phthiocerol dimycocerosates (PDIMs) are hallmark virulence-associated lipids within the Mycobacterium tuberculosis complex, including M. bovis. The ability to produce PDIMs depends on the presence of the ppsA-ppsE gene cluster, which harbors a series of modular type I PKS that coordinate the phthiocerol backbone of PDIMs. In this review, the genomic organization, biochemical function, and pathogenic relevance of the ppsA-ppsE cluster in M. bovis have been studied, integrating evidence from comparative genomics, lipid biochemistry, and host-pathogen interaction. In the M. tuberculosis complex, the 'pps' locus that houses the ppsA-ppsE gene cluster is found within a highly conserved gene cluster that coordinates the synthesis of PDIMs and also fatty acyl-AMP ligases, accessory enzymes, and specific lipid transporters. Therefore, the coordinated synthesis of M. tuberculosis complex lipids can be appreciated. In terms of pathogenesis, when the pps genes are mutated in M. bovis, the ability to synthesize PDIMs is reduced, the permeability of the bacterial envelope is increased, resistance to host-derived stresses reduced, and the overall capacity to cause disease is significantly diminished in both cellular and animal model studies. PDIMs contribute to immune evasion by masking Toll-like receptor signalling, pathogen-associated molecular pattern structures, resisting nitrosative and oxidative stress, and controlling phagosome maturation and the process of autophagy. Comparative analysis shows the 'absence' of the ppsA-ppsE gene cluster in M. avium subsp. paratuberculosis, underscoring divergent evolutionary strategies for host persistence among pathogenic mycobacteria. Collective studies underscore the importance of the ppsA-ppsE gene cluster's central role in the resulting process of lipid-mediated virulence.