Francisella tularensis(Ft), a Gram-negative intracellular bacterium, is the etiologic agent of tularemia. Infection of mice with <10FtLive Vaccine Strain (FtLVS) organisms i.p. causes a lethal infection that resembles human tularemia. Here, we show that immunization with as little as 0.1 ngFtLVS lipopolysaccharide (Ft-LPS), but notFtlipid A, generates a rapid antibody response that protects wild-type (WT) mice against lethalFtLVS challenge. Protection is not induced inFt-LPS-immunized B cell-deficient mice (μMT or JhD), malexidmice, or Ig transgenic mice that produce a single IgH (not reactive withFt-LPS). Focusing on the cellular mechanisms that underlie this protective response, we show thatFt-LPS specifically stimulates proliferation of B-1a lymphocytes that bind fluorochrome-labeledFt-LPS and the differentiation of these cells to plasma cells that secrete antibodies specific forFt-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 ≈5 days afterFt-LPS immunization and persist at low levels for months. Thus, immunization withFt-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 lethalFtLVS infection. These data support the possibility of creating effective, minimally invasive vaccines that can provide effective protection against pathogen invasion.

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