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pH-responsive substrate switching in mycobacterial type VII ESX secretion.

Owen A Collars1, Richard L Hernandez1,2, Simon D Weaver1,2

  • 1Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.

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Summary

Pathogenic mycobacteria like Mycobacterium marinum adapt to host environments by switching the proteins secreted by the ESX-1 system. This substrate switching, triggered by acidic pH, helps bacteria lyse phagosomes and promote infection.

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Area of Science:

  • Microbiology
  • Cell Biology
  • Pathogen-Host Interactions

Background:

  • Pathogenic mycobacteria, including those causing tuberculosis, reside in host macrophages within phagosomes.
  • The ESX-1 secretion system (early secreted antigen 6 kilodaltons [ESAT-6] system 1) is crucial for mycobacterial virulence, enabling phagosome lysis and bacterial escape.
  • The mechanisms by which ESX-1 functions in diverse phagosomal environments are not fully understood.

Purpose of the Study:

  • To investigate how the ESX-1 secretion system functions in varying pH conditions relevant to macrophage infection.
  • To determine if mycobacteria switch the proteins they secrete via ESX-1 in response to environmental cues like acidic pH.
  • To elucidate the molecular changes associated with ESX-1 substrate switching and its relevance during infection.

Main Methods:

  • Culturing *Mycobacterium marinum* at different pH levels *in vitro* to observe substrate secretion.
  • Analyzing changes in ESX-1 substrate and chaperone transcript and protein levels.
  • Utilizing *in vivo* infection models to assess the role of ESX-1 substrate switching during infection.

Main Results:

  • *Mycobacterium marinum* exhibits ESX-1 substrate switching when grown at acidic pH *in vitro*.
  • Substrate switching correlates with significant alterations in ESX-1 substrate and chaperone transcript and protein expression.
  • *In vivo* studies revealed upregulation of specific ESX-1 transcripts and demonstrated the requirement for distinct substrate sets in an acidic infection model.

Conclusions:

  • The ESX-1 secretion system dynamically orchestrates substrate switching in response to environmental pH.
  • Mycobacterial pathogens likely employ distinct ESX-1 protein sets to lyse macrophage phagosomes of differing acidity during infection.
  • Understanding ESX-1 substrate switching provides insights into mycobacterial pathogenesis and potential therapeutic targets.