title: Mycobacterium tuberculosis heat shock proteins use diverse Toll-like receptor pathways to activate pro-inflammatory signals.
abstract: Although the Toll-like receptors used by Mycobacterium tuberculosis membrane and secreted factors are known, the pathways activated by M. tuberculosis heat shock proteins are not. An efficient immune response against the intracellular pathogen M. tuberculosis is critically dependent on rapid detection of the invading pathogen by the innate immune system and coordinated activation of the adaptive immune response. Macrophage phagocytosis of M. tuberculosis is accompanied by activation of the transcription factor NF-kappaB and secretion of inflammatory mediators that play an important role in granuloma formation and immune protection during M. tuberculosis infection. The interaction between M. tuberculosis and the various Toll-like receptors is complex, and it appears that distinct mycobacterial components may interact with different members of the Toll-like receptor family. Here we show that recombinant, purified, mycobacterial heat shock proteins 65 and 70 induce NF-kappaB activity in a dose-dependent manner in human endothelial cells. Furthermore, we show that whereas mycobacterial heat shock protein 65 signals exclusively through Toll-like receptor 4, heat shock protein 70 also signals through Toll-like receptor 2. Mycobacterial heat shock protein 65-induced NF-kappaB activation was MyD88-, TIRAP-, TRIF-, and TRAM-dependent and required the presence of MD-2. A better understanding of the recognition of mycobacterial heat shock proteins and their role in the host immune response to the pathogen may open the way to a better understanding of the immunological processes induced by this important human pathogen and the host-pathogen interactions and may help in the rational design of more effective vaccines or vaccine adjuvants.
authors.affiliation: Division of Pediatric Critical Care, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California 90048, USA.
authors.forename: Yonca
authors.initials: Y
authors.lastname: Bulut
authors.forename: Kathrin S
authors.initials: KS
authors.lastname: Michelsen
authors.forename: Linda
authors.initials: L
authors.lastname: Hayrapetian
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Naiki
authors.forename: Ralf
authors.initials: R
authors.lastname: Spallek
authors.forename: Mahavir
authors.initials: M
authors.lastname: Singh
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D002478:Cells, Cultured; D018834:Chaperonin 60; D018833:Chaperonins / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D005799:Genes, Dominant; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007107:Immune System; D007249:Inflammation; D018950:Lipopolysaccharide Receptors / Q000737:chemistry; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010587:Phagocytosis; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D012867:Skin / Q000378:metabolism / Q000382:microbiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection
chemical_list: D001426:Bacterial Proteins; D018834:Chaperonin 60; D018076:DNA, Complementary; D018840:HSP70 Heat-Shock Proteins; C444642:HSP70 protein, Mycobacterium tuberculosis; D006360:Heat-Shock Proteins; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010455:Peptides; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C074119:heat-shock protein 65, Mycobacterium; D018833:Chaperonins