title: Synergistic interactions of TLR2/6 and TLR9 induce a high level of resistance to lung infection in mice.
abstract: Infectious pneumonias exact an unacceptable mortality burden worldwide. Efforts to protect populations from pneumonia have focused historically on antibiotic development and vaccine-enhanced adaptive immunity. However, we have reported recently that the lungs' innate defenses can be induced therapeutically by inhalation of a bacterial lysate that protects mice against otherwise lethal pneumonia. In this study, we tested in mice the hypothesis that TLRs are required for this antimicrobial phenomenon and found that resistance could not be induced in the absence of the TLR signaling adaptor protein MyD88. We then attempted to recapitulate the protection afforded by the bacterial lysate by stimulating the lung epithelium with aerosolized synthetic TLR ligands. Although most single or combination treatments yielded no protection, simultaneous treatment with ligands for TLR2/6 and TLR9 conferred robust, synergistic protection against virulent gram-positive and gram-negative pathogens. Protection was associated with rapid pathogen killing in the lungs, and pathogen killing could be induced from lung epithelial cells in isolation. Taken together, these data demonstrate the requirement for TLRs in inducible resistance against pneumonia, reveal a remarkable, unanticipated synergistic interaction of TLR2/6 and TLR9, reinforce the emerging evidence supporting the antimicrobial capacity of the lung epithelium, and may provide the basis for a novel clinical therapeutic that can protect patients against pneumonia during periods of peak vulnerability.
authors.affiliation: Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Duggan
authors.forename: Dahui
authors.initials: D
authors.lastname: You
authors.forename: Jeffrey O
authors.initials: JO
authors.lastname: Cleaver
authors.forename: Derek T
authors.initials: DT
authors.lastname: Larson
authors.forename: R Joshua
authors.initials: RJ
authors.lastname: Garza
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Guzmán Pruneda
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tuvim
authors.forename: Jiexin
authors.initials: J
authors.lastname: Zhang
authors.forename: Burton F
authors.initials: BF
authors.lastname: Dickey
authors.forename: Scott E
authors.initials: SE
authors.lastname: Evans
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004847:Epithelial Cells / Q000276:immunology; D005260:Female; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D051216:Toll-Like Receptor 6 / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D051217:Toll-Like Receptor 9; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; C495370:Tlr9 protein, mouse