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* Department of Medical Microbiology and Infection Control, VU University Medical Centre, Amsterdam,
Department of Immunohematology & Blood Transfusion, and Department of Infectious Diseases, Leiden University Medical Centre, Leiden,
The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
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
). 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-
, 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-1β 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. 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 response at various critical steps.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The work was supported by European Union Grant LSHP-CT-2003-503367 (TB-VAC Project) for work performed in the Ottenhoff laboratory. The work of T.H.M.O., N.D.L.S., and N.N.v.d.W. was supported by the Netherlands Leprosy Relief Foundation.
2 A.M.A. and N.D.L.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Wilbert Bitter, Department of Medical Microbiology and Infection Control, VU University Medical Centre, van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail address: w.bitter{at}vumc.nl
4 Abbreviations used in this paper: M, macrophage; MOI, multiplicity of infection; DC, dendritic cell; MoDC, monocyte-derived DC; PGRS, polymorphic GC-rich repetitive sequence; PI, propidium iodide; wt, wild type.
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