The ESX-5 secretion system of Mycobacterium marinum modulates the macrophage response

A.M. Abdallah, N.D. Savage, M. van Zon, L. Wilson, C.M.J.E. Vandenbroucke-Grauls, N.N. van der Wel, TH Ottenhoff, W. Bitter, Tom H. M. Ottenhoff

Research output: Contribution to journalArticleAcademicpeer-review

84 Citations (Scopus)


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 (M phi). 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-1 beta 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 M phi. 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 M phi response at various critical steps. The Journal of Immunology, 2008, 181: 7166-7175
Original languageEnglish
Pages (from-to)7166-7175
JournalJournal of Immunology
Issue number10
Publication statusPublished - 2008

Cite this