title: Lack of in vitro and in vivo recognition of Francisella tularensis subspecies lipopolysaccharide by Toll-like receptors.
abstract: Francisella tularensis is an intracellular gram-negative bacterium that is highly infectious and potentially lethal. Several subspecies exist of varying pathogenicity. Infection by only a few organisms is sufficient to cause disease depending on the model system. Lipopolysaccharide (LPS) of gram-negative bacteria is generally recognized by Toll-like receptor 4 (TLR4)/MD-2 and induces a strong proinflammatory response. Examination of human clinical F. tularensis isolates revealed that human virulent type A and type B strains produced lipid A of similar structure to the nonhuman model pathogen of mice, Francisella novicida. F. novicida LPS or lipid A is neither stimulatory nor an antagonist for human and murine cells through TLR4 or TLR2. It does not appear to interact with TLR4 or MD-2, as it is not an antagonist to other stimulatory LPS. Consistent with these observations, aerosolization of F. novicida LPS or whole bacteria induced no inflammatory response in mice. These results suggest that poor innate recognition of F. tularensis allows the bacterium to evade early recognition by the host innate immune system to promote its pathogenesis for mammals.
authors.affiliation: Department of Medicine, University of Washington, Health Sciences Building, Box 357710, 1959 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Adeline M
authors.initials: AM
authors.lastname: Hajjar
authors.forename: Megan D
authors.initials: MD
authors.lastname: Harvey
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shaffer
authors.forename: David R
authors.initials: DR
authors.lastname: Goodlett
authors.forename: Anders
authors.initials: A
authors.lastname: Sjöstedt
authors.forename: Helen
authors.initials: H
authors.lastname: Edebro
authors.forename: Mats
authors.initials: M
authors.lastname: Forsman
authors.forename: Mona
authors.initials: M
authors.lastname: Byström
authors.forename: Mark
authors.initials: M
authors.lastname: Pelletier
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Wilson
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Miller
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Skerrett
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005604:Francisella tularensis / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D008050:Lipid A / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D009000:Monocytes / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000502:physiology*
chemical_list: D008050:Lipid A; D008070:Lipopolysaccharides; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4