NF-kappa B activation controls phagolysosome fusion-mediated killing of mycobacteria by macrophages.
Macrophages can potentially kill all mycobacteria by poorly understood mechanisms. In this study, we explore the role of NF-kappaB 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-kappaB that is essential for maturation of mycobacterial phagosomes and bacterial killing. In contrast, the pathogenic M. avium partially represses NF-kappaB activation. Using microarray analysis, we identified many lysosomal enzymes and membrane-trafficking regulators, including cathepsins, LAMP-2 and Rab34, were regulated by NF-kappaB during infection. Our results argue that NF-kappaB activation increases the synthesis of membrane trafficking molecules, which may be rate limiting for regulating phagolysosome fusion during infection. The direct consequence of NF-kappaB inhibition is the impaired delivery of lysosomal enzymes to M. smegmatis phagosomes and reduced killing. Thus, the established role of NF-kappaB in the innate immune response can now be expanded to include regulation of membrane trafficking during infection.
Gutierrez
Maximiliano Gabriel
MG
European Molecular Biology Laboratory, Heidelberg, Germany. mgutierr@embl.de
Mishra
Bibhuti B
BB
Jordao
Luisa
L
Elliott
Edith
E
Anes
Elsa
E
Griffiths
Gareth
G
D000818:Animals; D002460:Cell Line; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D008247:Lysosomes / Q000201:enzymology / Q000276:immunology / Q000382:microbiology*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D009162:Mycobacterium avium / Q000254:growth & development / Q000276:immunology*; D020102:Mycobacterium smegmatis / Q000254:growth & development / Q000276:immunology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D010587:Phagocytosis / Q000276:immunology*; D010588:Phagosomes / Q000276:immunology / Q000382:microbiology*; D015398:Signal Transduction / Q000276:immunology
D018836:Inflammation Mediators; D016328:NF-kappa B