Antigen-specific B-1a antibodies induced by Francisella tularensis LPS provide long-term protection against F. tularensis LVS challenge

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 11; pp. 4343 - 4348
• Main Authors: Cole, Leah E, Yang, Yang, Elkins, Karen L, Fernandez, Ellen T, Qureshi, Nilofer, Shlomchik, Mark J, Herzenberg, Leonard A, Herzenberg, Leonore A, Vogel, Stefanie N
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.03.2009; National Acad Sciences
• Subjects: Animals; Antibodies; Antibodies, Bacterial; Antibody Formation; Antigens; Antigens, Bacterial; B lymphocytes; B-Lymphocytes - immunology; Bacterial Vaccines - administration & dosage; Bacterial Vaccines - immunology; Bacterial Vaccines - therapeutic use; Biological Sciences; Cells; Francisella tularensis; Francisella tularensis - immunology; Immunization; Infections; Lipids; Lipopolysaccharides - immunology; Lymphocyte Activation; Lymphocyte receptors; Mice; Mice, Knockout; Plasma cells; Rodents; Spleen; T lymphocytes; Tularemia - prevention & control; Vaccines
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0813411106

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 (μMT 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 (TCRαβ⁻/⁻, TCRγδ⁻/⁻), 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 [almost equal to]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.