Antigen- specific B-1a antibodies induced by Francisella tularensis LPS provide long-term protection against F. tularensis LVS challenge
Antigen- specific B-1a antibodies induced by Francisella tularensis LPS provide long-term protection against F. tularensis LVS challenge
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DOI：
10.1073/pnas.0813411106
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发表时间：
2009-03-17
影响因子：
11.1
通讯作者：
Vogel, Stefanie N.
中科院分区：
文献类型：
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作者：
Cole, Leah E.;Yang, Yang;Vogel, Stefanie N.
土拉热弗朗西丝菌（Francisellatularensis，Ft）是一种革兰氏阴性的胞内细菌，是土拉菌病的病原体。用< 10 Ft活疫苗株（Ft LVS）生物体i. p.感染小鼠引起类似于人兔热病的致死性感染。在这里，我们表明，免疫接种低至0.1 ng Ft LVS脂多糖（Ft-LPS），但不是Ft脂质A，产生快速的抗体反应，保护野生型（WT）小鼠对致命的Ft LVS的挑战。在Ft-LPS免疫的B细胞缺陷小鼠（μ MT或JhD）、雄性xid小鼠或产生单一IgH（不与Ft-LPS反应）的IG转基因小鼠中未诱导保护作用。关注这种保护性反应的细胞机制，我们发现Ft-LPS特异性地刺激结合荧光染料标记的Ft-LPS的B-1a淋巴细胞的增殖，并使这些细胞分化为分泌Ft-LPS特异性抗体的浆细胞。这种排他的B-1a抗体应答在WT、T缺陷（TCR α β（-/-）、TCR γ δ（-/-））和Toll样受体4（TLR 4）缺陷（TLR 4（-/-））小鼠中是等效的，因此不依赖于T细胞或典型的炎症过程。血清抗体水平在Ft-LPS免疫后约5天达到峰值，并在低水平持续数月。因此，用Ft-LPS免疫激活抗原特异性B-1a细胞的稀有群体以产生持久的T非依赖性抗体应答，其提供针对致死性Ft LVS感染的长期保护。这些数据支持了创造有效的、微创的疫苗的可能性，这些疫苗可以提供有效的保护，防止病原体入侵。
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 (mu MT 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 fluoro-chrome-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 (TCR alpha beta(-/-), TCR gamma delta(-/-)), 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 approximate 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.