Generation of a convalescent model of virulent Francisella tularensis infection for assessment of host requirements for survival of tularemia.
Generation of a convalescent model of virulent Francisella tularensis infection for assessment of host requirements for survival of tularemia.
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DOI：
10.1371/journal.pone.0033349
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Bosio CM
中科院分区：
文献类型：
--
作者：
Crane DD;Scott DP;Bosio CM
图拉氏方济氏菌是一种兼性胞内细菌，是图拉热病的病原体。由于缺乏对哪些免疫成分才能在感染中幸存下来的了解，图拉热症新疫苗和治疗方法的开发一直受到阻碍。确定这些保护图拉氏F菌(如SchuS4菌株)的要求一直很困难，因为实验感染的动物通常在接触10个细菌后5天内死亡。如此短的平均死亡时间通常排除了针对毒力图拉氏肺吸虫的免疫反应的发展，因此也就不能进行评估。为了能够识别毒力较强的图拉氏菌生存所需的免疫系统组件，我们使用低剂量抗生素治疗建立了C57BL/6小鼠图拉热症的恢复期模型，在该模型中，宿主免疫反应最终负责清除细菌。利用这个模型，我们证明了αβTcr+细胞、γδTcr+细胞和B细胞是原始SchuS4感染生存所必需的。对缺乏特定可溶性介质的小鼠的分析表明，IL-12p40和IL-12p35对于SchuS4感染的生存是必不可少的。我们还表明，干扰素-γ对于SchuS4感染的生存是必需的，因为缺乏干扰素-γR的小鼠在抗生素治疗过程中会屈服于疾病。最后，我们发现CD_4~+和CD_8~+细胞都是干扰素-γ的主要产生细胞，而γδT细胞受体~+细胞和NK细胞在整个感染过程中对这种细胞因子的产生贡献很小。综上所述，这些数据提供了一种新的模型，可以确定图拉氏F菌感染的生存或恶化所需的关键细胞和细胞因子，并提供证据表明，该模型将是更好地理解图拉热病感染动态的有用工具。
Francisella tularensis is a facultative intracellular bacterium and the causative agent of tularemia. Development of novel vaccines and therapeutics for tularemia has been hampered by the lack of understanding of which immune components are required to survive infection. Defining these requirements for protection against virulent F. tularensis, such as strain SchuS4, has been difficult since experimentally infected animals typically die within 5 days after exposure to as few as 10 bacteria. Such a short mean time to death typically precludes development, and therefore assessment, of immune responses directed against virulent F. tularensis. To enable identification of the components of the immune system that are required for survival of virulent F. tularensis, we developed a convalescent model of tularemia in C57Bl/6 mice using low dose antibiotic therapy in which the host immune response is ultimately responsible for clearance of the bacterium. Using this model we demonstrate αβTCR+ cells, γδTCR+ cells, and B cells are necessary to survive primary SchuS4 infection. Analysis of mice deficient in specific soluble mediators shows that IL-12p40 and IL-12p35 are essential for survival of SchuS4 infection. We also show that IFN-γ is required for survival of SchuS4 infection since mice lacking IFN-γR succumb to disease during the course of antibiotic therapy. Finally, we found that both CD4+ and CD8+ cells are the primary producers of IFN-γand that γδTCR+ cells and NK cells make a minimal contribution toward production of this cytokine throughout infection. Together these data provide a novel model that identifies key cells and cytokines required for survival or exacerbation of infection with virulent F. tularensis and provides evidence that this model will be a useful tool for better understanding the dynamics of tularemia infection.
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