[Induction of direct antimicrobial activity through mammalian toll-like receptors].
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.
Stenger
S
S
Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander Universität Erlangen-Nürnberg, Germany. steffen.stenger@mikrobio.med.uni-erlangen.de
Engele
M
M
Bölcskei
P L
PL
Röllinghoff
M
M
Wagner
M
M
D000818:Animals; D002460:Cell Line; D029721:Drosophila Proteins; D006801:Humans; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009569:Nitric Oxide / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014388:Tuberculosis, Lymph Node / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D009569:Nitric Oxide