Immunome Research
Open Access
ISSN: 1745-7580
ISSN: 1745-7580
Mohd Shariq, Nasreen Z. Ehtesham, Yashika Ahuja, Anwar Alam, Diksha Thakuri, Haleema Fayaz, Gauri Shrivastava, Javaid Ahmad Sheikh and Seyed E. Hasnain*
Mycobacterium tuberculosis (Mtb), the etiological agent of Tuberculosis (TB), has evolved sophisticated strategies to survive and persist within host macrophages despite robust innate and adaptive immune defenses. A growing body of evidence highlights the crucial role of the Proline-Glutamic Acid/Proline-Proline-Glutamic Acid (PE/ PPE) family of proteins, unique to pathogenic mycobacteria and constituting nearly 10% of the Mtb genome, in orchestrating immune evasion. Among the host defense pathways targeted by Mtb, autophagy has emerged as a critical cell-intrinsic antimicrobial mechanism that restricts intracellular bacterial growth and facilitates antigen presentation. However, virulent Mtb strains actively suppress autophagy through diverse molecular strategies, many of which are mediated by PE/PPE proteins. In this Review, we synthesize genomic, structural, molecular, and immunological evidence demonstrating how PE/PPE proteins function as master regulators of autophagy, apoptosis, ubiquitin signaling, and inflammatory responses. We integrate mechanistic paradigms involving PE_PGRS47- and PE_PGRS20-mediated inhibition of canonical autophagy, PPE51-driven rewiring of TLR2-MAPK signaling, PE6-dependent MTOR activation, and the paradoxical ubiquitin-dependent xenophagy mediated by Rv1468c. We propose a unifying model in which PE/PPE proteins act as modular effectors that fine-tune autophagy and immune signaling to promote long-term persistence, facilitate drug tolerance, and enable transmission. Finally, we discuss the translational implications of targeting PE/PPE-autophagy interfaces for host-directed therapies, vaccine design, and biomarker development in drug-resistant TB.
Published Date: 2025-02-05; Received Date: 2026-01-16