title: Antigen-specific B-1a antibodies induced by Francisella tularensis LPS provide long-term protection against F. tularensis LVS challenge.
abstract: Francisella tularensis (Ft), a gram-negative intracellular bacterium, is the etiologic agent of tularemia. Infection of mice with <10 Ft Live Vaccine Strain (Ft LVS) organisms i.p. causes a lethal infection that resembles human tularemia. Here, we show that immunization with as little as 0.1 ng Ft LVS lipopolysaccharide (Ft-LPS), but not Ft lipid A, generates a rapid antibody response that protects wild-type (WT) mice against lethal Ft LVS challenge. Protection is not induced in Ft-LPS-immunized B cell-deficient mice (muMT or JhD), male xid mice, or Ig transgenic mice that produce a single IgH (not reactive with Ft-LPS). Focusing on the cellular mechanisms that underlie this protective response, we show that Ft-LPS specifically stimulates proliferation of B-1a lymphocytes that bind fluorochrome-labeled Ft-LPS and the differentiation of these cells to plasma cells that secrete antibodies specific for Ft-LPS. This exclusively B-1a antibody response is equivalent in WT, T-deficient (TCRalphabeta(-/-), TCRgammadelta(-/-)), and Toll-like receptor 4 (TLR4)-deficient (TLR4(-/-)) mice and thus is not dependent on T cells or typical inflammatory processes. Serum antibody levels peak approximately 5 days after Ft-LPS immunization and persist at low levels for months. Thus, immunization with Ft-LPS activates a rare population of antigen-specific B-1a cells to produce a persistent T-independent antibody response that provides long-term protection against lethal Ft LVS infection. These data support the possibility of creating effective, minimally invasive vaccines that can provide effective protection against pathogen invasion.
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: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Karen L
authors.initials: KL
authors.lastname: Elkins
authors.forename: Ellen T
authors.initials: ET
authors.lastname: Fernandez
authors.forename: Nilofer
authors.initials: N
authors.lastname: Qureshi
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Herzenberg
authors.forename: Leonore A
authors.initials: LA
authors.lastname: Herzenberg
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial; D000917:Antibody Formation; D000942:Antigens, Bacterial; D001402:B-Lymphocytes / Q000276:immunology; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D005604:Francisella tularensis / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D014406:Tularemia / Q000517:prevention & control*
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001428:Bacterial Vaccines; D008070:Lipopolysaccharides