The Mycobacterium tuberculosis PE_PGRS Protein Family Acts as an Immunological Decoy to Subvert Host Immune Response

Abstract

Mycobacterium tuberculosis (M.tb) is a successful pathogen that can reside within the alveolar macrophages of the host and can survive in a latent stage. The pathogen has evolved and developed multiple strategies to resist the host immune responses. M.tb escapes from host macrophage through evasion or subversion of immune effector functions. M.tb genome codes for PE/PPE/PE_PGRS proteins, which are intrinsically disordered, redundant and antigenic in nature. These proteins perform multiple functions that intensify the virulence competence of M.tb majorly by modulating immune responses, thereby affecting immune mediated clearance of the pathogen. The highly repetitive, redundant and antigenic nature of PE/PPE/PE_PGRS proteins provide a critical edge over other M.tb proteins in terms of imparting a higher level of virulence and also as a decoy molecule that masks the effect of effector molecules, thereby modulating immuno-surveillance. An understanding of how these proteins subvert the host immunological machinery may add to the current knowledge about M.tb virulence and pathogenesis. This can help in redirecting our strategies for tackling M.tb infections.

PGRS domain structures: Doomed to sail the mycomembrane

“…Similarly, the PGRS domain of PE_PGRS31 interacts with S100A9 factor in macrophages to promote mycobacterial survival [ 23 ]. Similarly, our sailing model ensures an effective exposure of epitope regions in the PG II sandwich structure of the highly antigenic Wag22 [ 24 ] and similar considerations can be extended to other PE_PGRS proteins that have been proposed to serve as immunological decoys [ 25 ]. Indeed, the fact that PGRS domains are endowed with a well-structured fold make them even more suitable to serve as decoys, as they may expose structural motifs, with specific conformations, that act in the camouflage of effector molecules responsible for immune evasion [ 25 ].…”

Exploring Mycobacterium Tuberculosis Resistance Patterns to Antibiotics: A BV-BRC Study

“…The precise roles of many PE PGRS proteins are yet to be fully determined. The diversity of these proteins presents challenges for developing vaccines, necessitating immune responses that can effectively target a wide array of variants [40]. Notably, clofazimine is linked to four of these genes, while linezolid is linked to only one (PE PGRS4), also reported in CRyPTIC [43].…”

Role of MHC class I pathways in Mycobacterium tuberculosis antigen presentation

“…Specific Mtb proteins lack fixed conformational structure, e.g., the PGRS part in PE-PGRS proteins or the PPE part in PE-PPE proteins. This results in their nonspecific interference with host signaling pathways by allosteric mimicry ( Sharma et al., 2022 ). Cytosolic polyubiquitination of lysine residues in hydrophobic stretches of these proteins stabilizes their structure while directing them to the proteasome.…”