title: Toll-like receptor 4 expression is required to control chronic Mycobacterium tuberculosis infection in mice.
abstract: Endotoxin from Gram-negative bacteria bound to CD14 signals through Toll-like receptor (TLR) 4, while components of Gram-positive bacteria, fungi, and Mycobacterium tuberculosis (M.tb.) preferentially use TLR2 signaling. We asked whether TLR4 plays any role in host resistance to M.tb. infection in vivo. Therefore, we infected the TLR4 mutant C3H/HeJ mice and their controls, C3H/HeN mice, with M.tb. by aerosol. TLR4 mutant mice had a reduced capacity to eliminate mycobacteria from the lungs, spread the infection to spleen and liver, with 10-100 times higher CFU organ levels than the wild-type mice and succumbed within 5-7 mo, whereas most of the wild-type mice controlled infection and survived the duration of the experiment. The lungs of TLR4 mutant mice showed chronic pneumonia with increased neutrophil infiltration, reduced macrophages recruitment, and abundant acid-fast bacilli. Furthermore, the pulmonary expression of TNF-alpha, IL-12p40, and monocyte chemoattractant protein 1 was significantly lower in C3H/HeJ mice when compared with the wild-type controls. C3H/HeJ-derived macrophages infected in vitro with M.tb. produced lower levels of TNF-alpha. Finally, the purified mycobacterial glycolipid, phosphatidylinositol mannosides, induced signaling in both a TLR2- and TLR4-dependent manner, thus suggesting that recognition of phosphatidylinositol mannosides in vivo may influence the development of protective immunity. In summary, macrophage recruitment and the proinflammatory response to M.tb. are impaired in TLR4 mutant mice, resulting in chronic infection with impaired elimination of mycobacteria. Therefore, TLR4 signaling is required to mount a protective response during chronic M.tb. infection.
authors.affiliation: Department of Immunology, University of Cape Town, Cape Town, South Africa.
authors.forename: Brian
authors.initials: B
authors.lastname: Abel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Thieblemont
authors.forename: Valerie J F
authors.initials: VJ
authors.lastname: Quesniaux
authors.forename: Najmeeyah
authors.initials: N
authors.lastname: Brown
authors.forename: Joseph
authors.initials: J
authors.lastname: Mpagi
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Franck
authors.initials: F
authors.lastname: Bihl
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
mesh_terms: D000818:Animals; D001980:Bronchi / Q000276:immunology / Q000473:pathology; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002908:Chronic Disease; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D029721:Drosophila Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D010716:Phosphatidylinositols / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014376:Tuberculosis / Q000235:genetics / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D018925:Chemokines; D016207:Cytokines; D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010716:Phosphatidylinositols; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C034154:phosphatidylinositol mannoside