Induktion direkter antibakterieller Aktivität gegen Mycobacterium tuberculosis durch Toll-like-Rezeptoren

Zusammenfassung

Das Immunsystem des Menschen besitzt mit den Toll-like-Rezeptoren (TLR) eine ontogenetisch sehr alte Familie von Rezeptoren, über die bereits die Fruchtfliege verfügt. Sie reagieren auf Signale von mikrobiellen Liganden. In dieser Arbeit zeigen wir, dass die Aktivierung von TLR2 zu einer Eliminierung des intrazellulären Bakteriums Mycobacterium (M.) tuberculosis auch in humanen Makrophagen führt. In Mausmakrophagen führt die Aktivierung von TLR2 durch bakterielle Lipoproteine zur Induktion eines Effektormechanismus, der durch Stickoxid-Radikale vermittelt wird. In humanen Monozyten und Alveolarmakrophagen hingegen ist das Abtöten von M. tuberculosis Stickoxid-unabhängig. Daher interagieren die TLR von Säugern ähnlich wie das Toll-Protein von Drosophila mit mikrobiellen Liganden und aktivieren am Ort der Infektion antimikrobielle Effektormechanismen.

Abstract

Drosophila, the toll gene controls a powerful innate defense system against bacteria and fungi. Conserved through evolution, the mammalian innate immune system retains a family of homologous Toll-like receptors (TLRs) that are activated by microbial ligands to release cytokines that instruct the adaptive immune responses. Here we show that TLR2 activation leads to killing of intracellular Mycobacterium (M.) tuberculosis in both mouse and human macrophages. In mouse macrophages, bacterial lipoprotein activation of TLR2 leads to a nitric oxide-dependent killing of intracellular tubercle bacilli. In human monocytes and alveolar macrophages, bacterial lipoproteins similarly activated TLR2 to kill intracellular M. tuberculosis, however by an antimicrobial pathway that is nitric oxide independent. TLR2+CD14+CD68+ macrophages were detected in human lesions of tuberculous lymphadenitis within granulomas and surrounding foci of necrosis. These data provide evidence that mammalian TLRs have retained not only the structural features of Drosophila Toll that allow them to respond to microbial ligands, but also the ability directly to activate antimicrobial effector pathways at the site of infection.

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