Type VII Secretion Systems in Mycobacterial Pathogenesis

Type VII secretion systems (T7SSs) are specialised protein export machineries that underpin the virulence of pathogenic mycobacteria by translocating effectors across a complex cell envelope. Comprising five genetically distinct ESX (ESAT-6 secretion) loci, these systems mediate diverse roles in host–pathogen interactions, nutrient acquisition and immune modulation. The ESX-1 system facilitates phagolysosomal rupture and cytosolic access, enabling escape from macrophage confinement and induction of necrotic cell death. ESX-3 contributes to iron and zinc homeostasis, essential for bacterial growth under metal-limiting conditions. ESX-5 governs outer membrane permeability through secretion of surface PE/PPE proteins that influence cell envelope integrity and nutrient uptake. Recent structural studies have uncovered conserved C-terminal motifs that guide substrate recognition, while comparative genomics reveals extensive diversification via plasmid-encoded loci. Together, these discoveries highlight the centrality of T7SSs to the intracellular survival strategies of Mycobacterium tuberculosis and related species, offering potential targets for novel antimicrobial interventions.

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Type VII Secretion Systems in Mycobacterial Pathogenesis publication trend

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Technical terms

Type VII secretion system (T7SS): A specialised protein export pathway in mycobacteria, encoded by ESX loci, that translocates virulence factors across the cell envelope.

ESX-1/3/5: Distinct genetic loci encoding T7SS variants, each dedicated to specific functions such as phagosome rupture (ESX-1), metal acquisition (ESX-3) or outer membrane permeability (ESX-5).

Phagolysosomal rupture: Disruption of the phagosomal membrane by secreted effectors, permitting bacterial escape into the host cell cytosol.

PE/PPE proteins: A family of glycine-rich surface proteins secreted by ESX-5 that contribute to cell envelope stability and antigenic variation.

ESAT-6: A 6-kDa early secreted antigenic target protein, secreted by ESX-1, with membrane-lysing activity that facilitates host cell penetration.

Phagosome acidification: The process of lowering pH within the phagosome, which can trigger the activity of pH-responsive secreted effectors.

References

1. Phagosomal Rupture by Mycobacterium tuberculosis Results in Toxicity and Host Cell Death. PLOS Pathogens (2012).
2. Cytosolic Access of Mycobacterium tuberculosis: Critical Impact of Phagosomal Acidification Control and Demonstration of Occurrence In Vivo. PLOS Pathogens (2015).
3. The ESX-3 Secretion System Is Necessary for Iron and Zinc Homeostasis in Mycobacterium tuberculosis. PLOS ONE (2013).
4. Essential Role of the ESX-5 Secretion System in Outer Membrane Permeability of Pathogenic Mycobacteria. PLOS Genetics (2015).
5. Mycobacterial Pan-Genome Analysis Suggests Important Role of Plasmids in the Radiation of Type VII Secretion Systems. Genome Biology and Evolution (2016).
6. WXG100 Protein Superfamily Consists of Three Subfamilies and Exhibits an α-Helical C-Terminal Conserved Residue Pattern. PLOS ONE (2014).