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The Mycobacterium marinum ESX-1 system mediates phagosomal permeabilization and type I interferon production via separable mechanisms

Author:
  • Julia Lienard
  • Esther Nobs
  • Victoria Lovins
  • Elin Movert
  • Christine Valfridsson
  • Fredric Carlsson
Publishing year: 2020
Language: English
Pages: 1160-1166
Publication/Series: Proceedings of the National Academy of Sciences of the United States of America
Volume: 117
Issue: 2
Document type: Journal article
Publisher: National Acad Sciences

Abstract english

Following mycobacterial entry into macrophages the ESX-1 type VII secretion system promotes phagosomal permeabilization and type I IFN production, key features of tuberculosis pathogenesis. The current model states that the secreted substrate ESAT-6 is required for membrane permeabilization and that a subsequent passive leakage of extracellular bacterial DNA into the host cell cytosol is sensed by the cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) pathway to induce type I IFN production. We employed a collection of Mycobacterium marinum ESX-1 transposon mutants in a macrophage infection model and show that permeabilization of the phagosomal membrane does not require ESAT-6 secretion. Moreover, loss of membrane integrity is insufficient to induce type I IFN production. Instead, type I IFN production requires intact ESX-1 function and correlates with release of mitochondrial and nuclear host DNA into the cytosol, indicating that ESX-1 affects host membrane integrity and DNA release via genetically separable mechanisms. These results suggest a revised model for major aspects of ESX-1-mediated host interactions and put focus on elucidating the mechanisms by which ESX-1 permeabilizes host membranes and induces the type I IFN response, questions of importance for our basic understanding of mycobacterial pathogenesis and innate immune sensing.

Keywords

  • Microbiology in the medical area
  • Microbiology
  • ESAT-6 secretion
  • Membrane permeabilization
  • Mitochondrion
  • Mycobacterial pathogenesis
  • Type I interferon

Other

Published
  • Protein Chemistry, Malmö
  • Infectious Immunology
  • ISSN: 0027-8424
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E-mail: fredric [dot] carlsson [at] biol [dot] lu [dot] se

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