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Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane

William H Conrad1, Morwan M Osman1,2, Jonathan K Shanahan1,3

  • 1Department of Medicine, University of Cambridge, Cambridge CB2 0QH, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|January 26, 2017
PubMed

Insights

The ESX-1 secretion system, not ESAT-6 protein alone, causes host cell membrane lysis in Mycobacterium tuberculosis and marinum. This lysis is contact-dependent and involves gross membrane disruptions, not pores, requiring new research directions.

Area of Science:

  • Microbiology
  • Cell Biology
  • Pathogenesis

Background:

  • Mycobacterium tuberculosis and M. marinum virulence is linked to host cell membrane lysis.
  • The ESX-1 secretion system is crucial for both virulence and membrane lysis.
  • ESAT-6, an ESX-1 substrate, was previously thought to be pore-forming and lytic.

Purpose of the Study:

  • To re-evaluate the mechanism of ESX-1-mediated host cell membrane lysis.
  • To determine the role of ESAT-6 in the lytic activity of the ESX-1 system.
  • To characterize the morphological changes associated with ESX-1-dependent lysis.

Main Methods:

  • Investigated ESX-1 activity in Mycobacterium tuberculosis and M. marinum.
  • Tested recombinant ESAT-6 for eukaryotic cell membrane lytic activity.
  • Analyzed membrane disruptions using microscopy and characterized lysis mechanisms.

Main Results:

  • ESX-1, not recombinant ESAT-6 alone, mediates host cell membrane lysis.
  • Residual detergent in previous ESAT-6 preparations caused false-positive lytic results.
  • ESX-1-mediated lysis is contact-dependent, causes gross membrane disruptions, and is distinct from other secretion system lysis.

Conclusions:

  • The pore-forming activity of ESAT-6 is not responsible for ESX-1-mediated membrane lysis.
  • ESX-1-dependent lysis is a contact-mediated process involving significant membrane damage.
  • Further research is needed to elucidate the true mechanism of ESX-1-mediated lysis.
Keywords:
ESAT-6ESX-1 secretion systemMycobacterium marinumMycobacterium tuberculosiscell membrane lysis

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