title: Mycobacterium tuberculosis subverts innate immunity to evade specific effectors.
abstract: 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-gamma-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-kappaB 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-kappaB inhibitor abrogated the protection against FasL-mediated apoptosis, showing the implication of TLR2-mediated activation of NF-kappaB 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.
authors.affiliation: Institut de Microbiologie, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland. corinne.loeuillet@chuv.ch
authors.forename: Corinne
authors.initials: C
authors.lastname: Loeuillet
authors.forename: Fabio
authors.initials: F
authors.lastname: Martinon
authors.forename: Cynthia
authors.initials: C
authors.lastname: Perez
authors.forename: Miguel
authors.initials: M
authors.lastname: Munoz
authors.forename: Margot
authors.initials: M
authors.lastname: Thome
authors.forename: Pascal R
authors.initials: PR
authors.lastname: Meylan
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry; D002473:Cell Wall; D053222:Fas Ligand Protein / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016328:NF-kappa B / Q000819:agonists / Q000032:analysis / Q000037:antagonists & inhibitors; D053473:Nod2 Signaling Adaptor Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D010457:Peptidoglycan / Q000494:pharmacology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2