Immunologic consequences of Francisella tularensis live vaccine strain infection:: Role of the innate immune response in infection and immunity
Immunologic consequences of Francisella tularensis live vaccine strain infection:: Role of the innate immune response in infection and immunity
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DOI：
10.4049/jimmunol.176.11.6888
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发表时间：
2006-06-01
影响因子：
4.4
通讯作者：
Vogel, Stefanie N.
中科院分区：
文献类型：
--
作者：
Cole, Leah E.;Elkins, Karen L.;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。尽管对人类减毒，但用< 10 Ft活疫苗株（LVS）生物体腹膜内感染小鼠会导致类似于人兔热病的致死性感染，而皮内感染的LD 50> 10（6）个生物体。为了检查Ft LVS感染对先天免疫应答的免疫学后果，比较了腹膜内或皮内感染的小鼠的炎症应答。腹腔感染的小鼠表现出更大的细菌负荷和促炎基因的表达增加，特别是在肝脏中。与大多数LPS相反，发现高度纯化的Ft LVS LPS（10 μ g/ml）在原代鼠巨噬细胞和用TLR 4/MD-2/CD 14瞬时转染的HEK 293 T细胞中仅具有最低限度的刺激性，而活的Ft LVS细菌对巨噬细胞和表达TLR 2的HEK 293 T细胞具有高度刺激性。尽管体外Ft LVS LPS的刺激活性差，但在Ft LVS攻击前2天给予100 ng Ft LVS LPS严重限制了细菌负荷和细胞因子mRNA和蛋白质表达，在细菌攻击时不存在可检测的Ab，但这些小鼠在感染后2天内产生了稳健的Igm Ab应答并存活。这些数据表明，预先给予Ft LVS LPS可以通过减少细菌负荷和减弱压倒性的炎症反应来保护宿主，同时引发适应性免疫反应以产生强烈的Ab反应。
Francisella tularensis (Ft), a Gram-negative intracellular bacterium, is the etiologic agent of tularemia. Although attenuated for humans, i.p. infection of mice with < 10 Ft live vaccine strain (LVS) organisms causes lethal infection that resembles human tularemia, whereas the LD50 for an intradermal infection is > 10(6) organisms. To examine the immunological consequences of Ft LVS infection on the innate immune response, the inflammatory responses of mice infected i.p. or intradermally were compared. Mice infected i.p. displayed greater bacterial burden and increased expression of proinflammatory genes, particularly in the liver. In contrast to most LPS, highly purified Ft LVS LPS (10 mu g/ml) was found to be only minimally stimulatory in primary murine macrophages and in HEK293T cells transiently transfected with TLR4/MD-2/CD14, whereas live Ft LVS bacteria were highly stimulatory for macrophages and TLR2-expressing HEK293T cells. Despite the poor stimulatory activity of Ft LVS LPS in vitro, administration of 100 ng of Ft LVS LPS 2 days before Ft LVS challenge severely limited both bacterial burden and cytokine mRNA and protein expression in the absence of detectable Ab at the time of bacterial challenge, yet these mice developed a robust Igm Ab response within 2 days of infection and survived. These data suggest that prior administration of Ft LVS LPS protects the host by diminishing bacterial burden and blunting an otherwise overwhelming inflammatory response, while priming the adaptive immune response for development of a strong Ab response.