title: Role of TLR signaling in Francisella tularensis-LPS-induced, antibody-mediated protection against Francisella tularensis challenge.
abstract: Immunization with Ft-LPS provokes an antigen-specific, B-1a cell-derived antibody response that protects WT mice against an otherwise lethal challenge with Ft LVS. However, this same regimen offers limited protection to TLR2(-/-) mice, despite production of WT levels of anti-Ft-LPS antibodies. As Ft-LPS exhibits no TLR2 agonist activity, and macrophage-induced cytokine production in response to Ft LVS is overwhelmingly TLR2-dependent, we hypothesized that treatment of TLR2(-/-) mice with an alternative, MyD88-dependent TLR agonist would compensate for reduced recognition of Ft LVS in TLR2(-/-) mice and thereby, restore Ft-LPS-mediated protection. Administration of the nontoxic TLR4 agonist, synthetic Escherichia coli MPL, at the time of Ft-LPS immunization or Ft LVS challenge, fully protected TLR2(-/-) mice, whereas treatment of WT or TLR2(-/-) mice with MPL alone conferred partial protection. The TLR5 agonist, flagellin, also synergized with Ft-LPS to protect TLR2(-/-) mice from lethal Ft LVS challenge. In contrast to Ft LVS, Ft-LPS pretreatment failed to protect mice against i.n. challenge with Ft Schu S4, whereas MPL, administered in the absence or presence of Ft-LPS, conferred significant, albeit partial, protection. MPL treatment of macrophages increased the uptake of Ft LVS and decreased intracellular bacterial survival while shifting the macrophage-differentiation phenotype from "alternatively activated" to "classically activated". Collectively, our data suggest that optimal, Ft-LPS-mediated protection against Ft LVS infection requires two discrete events, i.e., production of Ft-LPS-specific antibody, as well as TLR-mediated macrophage activation, to fully control Francisella infection.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201, USA.
authors.forename: Leah E
authors.initials: LE
authors.lastname: Cole
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Mann
authors.forename: Kari Ann
authors.initials: KA
authors.lastname: Shirey
authors.forename: Katharina
authors.initials: K
authors.lastname: Richard
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Gearhart
authors.forename: Kirsty L
authors.initials: KL
authors.lastname: Chesko
authors.forename: Rose M
authors.initials: RM
authors.lastname: Viscardi
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000235:genetics / Q000276:immunology*; D005260:Female; D005604:Francisella tularensis / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D014406:Tularemia / Q000235:genetics / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4