title: The MyD88-dependent, but not the MyD88-independent, pathway of TLR4 signaling is important in clearing nontypeable haemophilus influenzae from the mouse lung.
abstract: TLRs are important for the recognition of conserved motifs expressed by invading bacteria. TLR4 is the signaling receptor for LPS, the major proinflammatory component of the Gram-negative cell wall, whereas CD14 serves as the ligand-binding part of the LPS receptor complex. Triggering of TLR4 results in the activation of two distinct intracellular pathways, one that relies on the common TLR adaptor MyD88 and one that is mediated by Toll/IL-1R domain-containing adaptor-inducing IFN-beta (TRIF). Nontypeable Haemophilus influenzae (NTHi) is a common Gram-negative respiratory pathogen that expresses both TLR4 (LPS and lipooligosaccharide) and TLR2 (lipoproteins) ligands. To determine the roles of CD14, TLR4, and TLR2 during NTHi pneumonia, the following studies were performed: 1) Alveolar macrophages from CD14 and TLR4 knockout (KO) mice were virtually unresponsive to NTHi in vitro, whereas TLR2 KO macrophages displayed a reduced NTHi responsiveness. 2) After intranasal infection with NTHi, CD14 and TLR4 KO mice showed an attenuated early inflammatory response in their lungs, which was associated with a strongly reduced clearance of NTHi from the respiratory tract; in contrast, in TLR2 KO mice, lung inflammation was unchanged, and the number of NTHi CFU was only modestly increased at the end of the 10-day observation period. 3) MyD88 KO, but not TRIF mutant mice showed an increased bacterial load in their lungs upon infection with NTHi. These data suggest that the MyD88-dependent pathway of TLR4 is important for an effective innate immune response to respiratory tract infection caused by NTHi.
authors.affiliation: Laboratory of Experimental Internal Medicine, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Catharina W
authors.initials: CW
authors.lastname: Wieland
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Nico A
authors.initials: NA
authors.lastname: Maris
authors.forename: Kasper
authors.initials: K
authors.lastname: Hoebe
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006193:Haemophilus influenzae / Q000276:immunology*; D007249:Inflammation / Q000209:etiology; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000943:Antigens, Differentiation; D018925:Chemokines; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse