The ESX-5 Secretion System of Mycobacterium Marinum Modulates the Macrophage Response

J Immunol. 2008 Nov 15;181(10):7166-75. doi: 10.4049/jimmunol.181.10.7166.

Abstract

The ESX-5 secretion system of pathogenic mycobacteria is responsible for the secretion of various PPE and PE-PGRS proteins. To better understand the role of ESX-5 effector proteins in virulence, we analyzed the interactions of Mycobacterium marinum ESX-5 mutant with human macrophages (Mphi). Both wild-type bacteria and the ESX-5 mutant were internalized and the ESX-5 mutation did not affect the escape of mycobacteria from phagolysosomes into the cytosol, as was shown by electron microscopy. However, the ESX-5 mutation strongly effected expression of surface Ags and cytokine secretion. Whereas wild-type M. marinum actively suppressed the induction of appreciable levels of IL-12p40, TNF-alpha, and IL-6, infection with the ESX-5 mutant resulted in strongly induced production of these proinflammatory cytokines. By contrast, infection with M. marinum wild-type strain resulted in a significant induction of IL-1beta production as compared with the ESX-5 mutant. These results show that ESX-5 plays an essential role in the modulation of immune cytokine secretion by human Mphi. Subsequently, we show that an intact ESX-5 secretion system actively suppresses TLR signaling-dependent innate immune cytokine secretion. Together, our results show that ESX-5 substrates, directly or indirectly, strongly modulate the human Mphi response at various critical steps.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / immunology*
  • Bacterial Proteins / metabolism
  • Carrier Proteins / immunology
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Humans
  • Immunoblotting
  • Macrophages / immunology*
  • Macrophages / microbiology*
  • Mycobacterium Infections, Nontuberculous / immunology*
  • Mycobacterium marinum / pathogenicity*
  • Virulence Factors / immunology*
  • Virulence Factors / metabolism

Substances

  • Bacterial Proteins
  • Carrier Proteins
  • Cytokines
  • Virulence Factors