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* Institut de Microbiologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
Département de Biochimie, Université de Lausanne, Lausanne, Switzerland; and
Service des Maladies Infectieuses, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
The macrophage is the niche of the intracellular pathogen Mycobacterium tuberculosis. Induction of macrophage apoptosis by CD4+ or CD8+ T cells is accompanied by reduced bacterial counts, potentially defining a host defense mechanism. We have already established that M. tuberculosis-infected primary human macrophages have a reduced susceptibility to Fas ligand (FasL)-induced apoptosis. To study the mechanisms by which M. tuberculosis prevents apoptotic signaling, we have generated a cell culture system based on PMA- and IFN-
-differentiated THP-1 cells recapitulating the properties of primary macrophages. In these cells, nucleotide-binding oligomerization domain 2 or TLR2 agonists and mycobacterial infection protected macrophages from apoptosis and resulted in NF-
B nuclear translocation associated with up-regulation of the antiapoptotic cellular FLIP. Transduction of a receptor-interacting protein-2 dominant-negative construct showed that nucleotide-binding oligomerization domain 2 is not involved in protection in the mycobacterial infection system. In contrast, both a dominant-negative construct of the MyD88 adaptor and an NF-B inhibitor abrogated the protection against FasL-mediated apoptosis, showing the implication of TLR2-mediated activation of NF-B in apoptosis protection in infected macrophages. The apoptosis resistance of infected macrophages might be considered as an immune escape mechanism, whereby M. tuberculosis subverts innate immunity signaling to protect its host cell against FasL+-specific cytotoxic lymphocytes.
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 This study was funded by Grant 3339-064166 from the Swiss National Science Foundation (to P.R.M.).
2 Address correspondence and reprint requests to Dr. Corinne Loeuillet, Institut de Microbiologie, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland. E-mail address: corinne.loeuillet{at}chuv.ch
3 Abbreviations used in this paper: FasL, Fas ligand; LAM, lipoarabinomannan; AraLAM, noncapped LAM; c-FLIP, cellular FLIP; CARD, caspase recruitment domain; ManLAM, mannose-capped LAM; MDP, muramyl dipeptide; Nod, nucleotide-binding oligomerization domain; PDTC, ammonium pyrrolidine dithiocarbamate; RIP2, receptor-interacting protein-2; TRAF, TNFR-associated factor.
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