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The C terminus of the mycobacterium ESX-1 secretion system substrate ESAT-6 is required for phagosomal membrane

Morwan M Osman1,2, Jonathan K Shanahan1,2, Frances Chu3

  • 1Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, CB2 OQH Cambridge, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|March 10, 2022
PubMed

Insights

The C terminus of ESAT-6 is crucial for Mycobacterium tuberculosis virulence. Its integrity is required for damaging macrophage phagosomes, forming granulomas, and causing disease.

Area of Science:

  • Microbiology
  • Immunology
  • Pathogenesis

Background:

  • Tuberculosis (TB) remains a significant global health threat, caused by Mycobacterium tuberculosis.
  • Mycobacteria infect and survive within macrophages, evading host defenses.
  • Phagosomal membrane damage by mycobacteria is essential for pathogenesis, mediated by the ESX-1 secretion system and its protein ESAT-6.

Purpose of the Study:

  • To investigate the role of the ESAT-6 C terminus in Mycobacterium tuberculosis pathogenesis.
  • To determine the structural requirements of ESAT-6 for macrophage phagosomal damage and virulence.

Main Methods:

  • Analysis of ESAT-6 C terminus integrity.
  • Assessment of macrophage phagosomal damage.
  • Evaluation of granuloma formation and virulence in a host model.

Main Results:

  • The integrity of the unstructured ESAT-6 C terminus is essential for its function.
  • Disruption of the ESAT-6 C terminus impairs phagosomal membrane damage.
  • Loss of ESAT-6 C terminus integrity reduces granuloma formation and overall virulence.

Conclusions:

  • The ESAT-6 C terminus is a critical virulence factor for Mycobacterium tuberculosis.
  • Maintaining ESAT-6 C terminus integrity is necessary for effective macrophage exploitation and disease progression.
Keywords:
ESAT-6ESX-1phagosomal damagevirulence

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