title: The ESX-5 secretion system of Mycobacterium marinum modulates the macrophage response.
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.
authors.affiliation: Department of Medical Microbiology and Infection Control, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Abdallah M
authors.initials: AM
authors.lastname: Abdallah
authors.forename: Nigel D L
authors.initials: ND
authors.lastname: Savage
authors.forename: Maaike
authors.initials: M
authors.lastname: van Zon
authors.forename: Louis
authors.initials: L
authors.lastname: Wilson
authors.forename: Christina M J E
authors.initials: CM
authors.lastname: Vandenbroucke-Grauls
authors.forename: Nicole N
authors.initials: NN
authors.lastname: van der Wel
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.forename: Wilbert
authors.initials: W
authors.lastname: Bitter
mesh_terms: D001426:Bacterial Proteins / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D015151:Immunoblotting; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D009165:Mycobacterium Infections, Nontuberculous / Q000276:immunology*; D019910:Mycobacterium marinum / Q000472:pathogenicity*; D037521:Virulence Factors / Q000276:immunology* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D016207:Cytokines; D037521:Virulence Factors