PE/PPE Protein Dynamics in Mycobacterium tuberculosis Pathogenesis

Mycobacterium tuberculosis harbours two expansive multigene families, designated PE and PPE, whose members collectively constitute around 10 % of the bacillary coding potential. These proteins are distinguished by conserved N-terminal Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs and, in many cases, downstream polymorphic glycine-rich domains. Functionally, PE/PPE proteins localise to the cell envelope or are secreted via specialised ESX secretion systems, mediating interactions with host innate immune receptors, modulating phagosome maturation and influencing cytokine induction. Polymorphism within PE_PGRS subfamilies drives antigenic variation, contributing both to immune evasion and lineage-specific adaptation. Emerging evidence indicates that distinct PE/PPE proteins reshape cell wall lipid composition to enhance environmental resilience, while others engage pattern-recognition receptors such as Toll-like receptor 2 or 4 to alter inflammasome activation. Collectively, these dynamics underpin M. tuberculosis persistence, transmission potential and the variable efficacy of vaccine and therapeutic strategies targeting the pathogen.

Research from Nature Portfolio

Investigation of the PE family member PE11 has revealed its integral role in remodelling the mycobacterial cell envelope and promoting virulence. Heterologous expression of PE11 in a non-pathogenic mycobacterial model altered colony morphology, increased the abundance of glycolipids and polar lipids, and conferred heightened resistance to oxidative stress and antibiotics. In macrophage infection assays, PE11-expressing bacteria exhibited improved intracellular survival, while in a murine model they induced elevated organ bacterial burdens, exacerbated pulmonary and hepatic pathology, and skewed cytokine responses towards anti-inflammatory profiles. These findings underscore that PE11 facilitates bacillary escape from host defences through cell wall modifications and immunomodulation, establishing a paradigm for how individual PE proteins can drive disease severity.

PE/PPE Protein Dynamics in Mycobacterium tuberculosis Pathogenesis publication trend

The graph below shows the total number of articles in pe/ppe protein dynamics in mycobacterium tuberculosis pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

PE/PPE proteins: Two multigene families in M. tuberculosis defined by PE (Pro-Glu) or PPE (Pro-Pro-Glu) motifs, often involved in immune modulation and antigenic variation.

PE_PGRS domain: A glycine-rich polymorphic region found in a subset of PE proteins, implicated in antigenic diversity and host-pathogen interaction.

Toll-like receptor 4 (TLR4): A pattern-recognition receptor on immune cells that detects pathogen-associated molecules and initiates inflammatory signalling.

NLRP3 inflammasome: A multiprotein complex in innate immune cells that activates caspase-1, processing pro-IL-1β into its active inflammatory form.

Homoplastic mutation: A genetic change that arises independently in multiple lineages, often associated with convergent adaptation.

References

1. PE12 interaction with TLR4 promotes intracellular survival of Mycobacterium tuberculosis by suppressing inflammatory response. International Journal of Biological Macromolecules (2023).
2. Immunological effects of the PE/PPE family proteins of Mycobacterium tuberculosis and related vaccines. Frontiers in Immunology (2023).
3. Structural Basis of PE_PGRS Polymorphism, a Tool for Functional Modulation. Biomolecules (2023).
4. Functional genetic variation in pe/ppe genes contributes to diversity in Mycobacterium tuberculosis lineages and potential interactions with the human host. Frontiers in Microbiology (2023).
5. PE/PPE mutations in the transmission of Mycobacterium tuberculosis in China revealed by whole genome sequencing. BMC Microbiology (2024).
6. PE11, a PE/PPE family protein of Mycobacterium tuberculosis is involved in cell wall remodeling and virulence. Scientific Reports (2016).
7. Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions. BMC Ecology and Evolution (2006).
8. Mycobacterial PE/PPE Proteins at the Host‐Pathogen Interface. Journal of Immunology Research (2011).
9. Execution of Macrophage Apoptosis by PE_PGRS33 of Mycobacterium tuberculosis Is Mediated by Toll-like Receptor 2-dependent Release of Tumor Necrosis Factor-α*. Journal of Biological Chemistry (2006).