The PE/PPE family proteins of Mycobacterium tuberculosis: evolution, function, and prospects for tuberculosis control

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading global health threat, exacerbated by drug resistance and inadequate vaccine efficacy. The PE/PPE protein family, unique to mycobacteria, constitutes ~10% of the Mtb genome and plays critical roles in bacterial physiology, immune evasion, and host-pathogen interactions. This review synthesizes advances in understanding the evolutionary expansion, structural diversity, and functional versatility of PE/PPE proteins, emphasizing their co-evolution with type VII secretion systems (T7SS). We highlight their roles in nutrient acquisition, immune modulation, and pathogenesis, alongside their potential as diagnostic and vaccine targets. Clinical progress in PE/PPE-based vaccines, such as M72/AS01E and ID93/GLA-SE, underscores their promise in combating TB, while challenges in epitope variability and functional redundancy demand innovative strategies. By integrating evolutionary, structural, and immunological insights, this review provides a roadmap for leveraging PE/PPE biology to develop next-generation TB interventions.

Keywords: Mycobacterium tuberculosis; PE/PPE; evolution; outer membrane; porin; vaccine.

Figure 1

Schematic representation of PE/PPE-mediated immunomodulatory mechanisms in host immune cells. PE/PPE family proteins mediate diverse immunomodulatory functions across multiple phases of Mtb-host interactions. Key mechanisms include: (1) Toll-like receptor (TLR) engagement to modulate downstream signaling cascades; (2) Disruption of phagosome maturation; (3) Interference with antigen presentation; (4) Neutralization of macrophage-derived reactive oxygen species (ROS)/nitric oxide (NO); (5) Regulation of autophagy through ubiquitin (Ub)-dependent pathways; (6) Modulation of programmed cell death; (7) Cytokine network manipulation; (8) Shaping of adaptive immunity. Green arrows: PE/PPE-induced processes, red blunt lines: PE/PPE-inhibited pathways.