title: Administration of a synthetic TLR4 agonist protects mice from pneumonic tularemia.
abstract: Francisella tularensis is a Gram-negative intracellular pathogen that causes the zoonosis tularemia. Because F. tularensis LPS causes weak TLR4 activation, we hypothesized that administration of a synthetic TLR4 agonist, aminoalkyl glucosaminide phosphate (AGP), would boost the innate immune system and compensate for reduced TLR4 stimulation. Intranasal administration of AGPs induced intrapulmonary production of proinflammatory cytokines and chemokines. Mice treated with AGPs before and after inhalation of Francisella novicida exhibited augmented cytokine and inflammatory responses to infection; reduced bacterial replication in lung, liver, and spleen; and increased survival, whereas all PBS-treated control mice died within 4 days of infection, all AGP-treated mice showed prolonged time-to-death, and 30-60% of AGP-treated mice survived. The protective effect of AGP was lost in mice lacking IFN-gamma. Long-term survivors developed specific Th1 splenocyte responses and specific Abs dominated by IgG2 isotypes. Survivors were fully protected from rechallenge with aerosolized F. novicida. Thus, preventive administration of AGP successfully modulated innate immune responses to aerosolized F. novicida, leading to protective immunity to pneumonic tularemia. This is the first report of the protective effect of a TLR ligand on resistance to F. novicida-induced pneumonic tularemia.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98104, USA.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Lembo
authors.forename: Mark
authors.initials: M
authors.lastname: Pelletier
authors.forename: Ravi
authors.initials: R
authors.lastname: Iyer
authors.forename: Michele
authors.initials: M
authors.lastname: Timko
authors.forename: Jan C
authors.initials: JC
authors.lastname: Dudda
authors.forename: T Eoin
authors.initials: TE
authors.lastname: West
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Wilson
authors.forename: Adeline M
authors.initials: AM
authors.lastname: Hajjar
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Skerrett
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D018893:Bronchoalveolar Lavage; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005604:Francisella tularensis / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D005944:Glucosamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009943:Organophosphorus Compounds / Q000008:administration & dosage*; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000517:prevention & control; D013154:Spleen / Q000382:microbiology; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D014406:Tularemia / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control
chemical_list: C530111:AGP 524; C530112:AGP 527; D016207:Cytokines; D009943:Organophosphorus Compounds; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma; D005944:Glucosamine