Cutting edge: a Toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling.
Toll-like receptors (TLRs) are key mediators of the innate immune response to microbial pathogens. We investigated the role of TLRs in the recognition of Mycobacterium leprae and the significance of TLR2Arg(677)Trp, a recently discovered human polymorphism that is associated with lepromatous leprosy. In mice, TNF-alpha production in response to M. leprae was essentially absent in TLR2-deficient macrophages. Similarly, human TLR2 mediated M. leprae-dependent activation of NF-kappaB in transfected Chinese hamster ovary and human embryonic kidney 293 cells, with enhancement of this signaling in the presence of CD14. In contrast, activation of NF-kappaB by human TLR2Arg(677)Trp was abolished in response to M. leprae and Mycobacterium tuberculosis. The impaired function of this TLR2 variant provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy and may have important implications for understanding the pathogenesis of other mycobacterial infections.
Bochud
Pierre-Yves
PY
Institute for Systems Biology, Seattle, WA 98103-8904, USA.
Hawn
Thomas R
TR
Aderem
Alan
A
D000818:Animals; D001120:Arginine / Q000235:genetics; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D015440:Leprosy, Lepromatous / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009166:Mycobacterium leprae / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology; D020641:Polymorphism, Single Nucleotide / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014364:Tryptophan / Q000235:genetics
D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014364:Tryptophan; D001120:Arginine