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NF-B Activation Controls Phagolysosome Fusion-Mediated Killing of Mycobacteria by Macrophages¹

Maximiliano Gabriel Gutierrez^2,3,*, Bibhuti B. Mishra^2,, Luisa Jordao, Edith Elliott, Elsa Anes and Gareth Griffiths^*

^* European Molecular Biology Laboratory, Heidelberg, Germany; Unidade de Retrovírus e Infecções Associadas-Centro de Patogénese Molecular Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal; and School of Biochemistry, Genetics, Microbiology and Plant Pathology, University of KwaZulu-Natal, Pietermaritzburg, South Africa

Macrophages can potentially kill all mycobacteria by poorly understood mechanisms. In this study, we explore the role of NF-B in the innate immune response of macrophages against Mycobacterium smegmatis, a nonpathogenic mycobacterium efficiently killed by macrophages, and Mycobacterium avium which survives within macrophages. We show that infection of macrophages with M. smegmatis induces an activation of NF-B that is essential for maturation of mycobacterial phagosomes and bacterial killing. In contrast, the pathogenic M. avium partially represses NF-B activation. Using microarray analysis, we identified many lysosomal enzymes and membrane-trafficking regulators, including cathepsins, LAMP-2 and Rab34, were regulated by NF-B during infection. Our results argue that NF-B activation increases the synthesis of membrane trafficking molecules, which may be rate limiting for regulating phagolysosome fusion during infection. The direct consequence of NF-B inhibition is the impaired delivery of lysosomal enzymes to M. smegmatis phagosomes and reduced killing. Thus, the established role of NF-B in the innate immune response can now be expanded to include regulation of membrane trafficking during infection.

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 M.G.G. was supported by a Research Fellowship from Alexander von Humboldt Foundation and is currently funded by an European Molecular Biology Organization Fellowship. E.A. was supported by Fundação para a Ciência e a tecnologia Grant POCI/BIA-BCM/55327/2004 with coparticipation of the European Union fund FEDER Programme POCI2010.

² M.G.G. and B.B.M. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Maximiliano Gabriel Gutierrez, European Molecular Biology Laboratory, Postfach 102209, 69117 Heidelberg, Germany. E-mail address: mgutierr{at}embl.de

⁴ Abbreviations used in this paper: siRNA, small interfering RNA; qRT-PCR, quantitative real-time PCR; BMM, bone marrow macrophage; Cts, cathepsin; Gla, -galactosidase.