Lembo Annalisa, Pelletier Mark, Iyer Ravi, Timko Michele, Dudda Jan C, West T Eoin, Wilson Christopher B, Hajjar Adeline M, Skerrett Shawn J
Department of Medicine, University of Washington, Seattle, WA 98104, USA.
J Immunol. 2008 Jun 1;180(11):7574-81. doi: 10.4049/jimmunol.180.11.7574.
Francisella tularensis is a Gram-negative intracellular pathogen that causes the zoonosis tularemia. Because F. tularensis LPS causes weak TLR4 activation, we hypothesized that administration of a synthetic TLR4 agonist, aminoalkyl glucosaminide phosphate (AGP), would boost the innate immune system and compensate for reduced TLR4 stimulation. Intranasal administration of AGPs induced intrapulmonary production of proinflammatory cytokines and chemokines. Mice treated with AGPs before and after inhalation of Francisella novicida exhibited augmented cytokine and inflammatory responses to infection; reduced bacterial replication in lung, liver, and spleen; and increased survival, whereas all PBS-treated control mice died within 4 days of infection, all AGP-treated mice showed prolonged time-to-death, and 30-60% of AGP-treated mice survived. The protective effect of AGP was lost in mice lacking IFN-gamma. Long-term survivors developed specific Th1 splenocyte responses and specific Abs dominated by IgG2 isotypes. Survivors were fully protected from rechallenge with aerosolized F. novicida. Thus, preventive administration of AGP successfully modulated innate immune responses to aerosolized F. novicida, leading to protective immunity to pneumonic tularemia. This is the first report of the protective effect of a TLR ligand on resistance to F. novicida-induced pneumonic tularemia.
土拉弗朗西斯菌是一种革兰氏阴性细胞内病原体，可引起人畜共患病土拉菌病。由于土拉弗朗西斯菌脂多糖引起的Toll样受体4（TLR4）激活较弱，我们推测给予合成的TLR4激动剂氨基烷基葡糖胺磷酸盐（AGP）会增强先天免疫系统并弥补TLR4刺激的减少。经鼻内给予AGP可诱导肺内促炎细胞因子和趋化因子的产生。在吸入新凶手弗朗西斯菌之前和之后用AGP处理的小鼠对感染表现出增强的细胞因子和炎症反应；肺、肝和脾中的细菌复制减少；存活率提高，而所有用磷酸盐缓冲盐水（PBS）处理的对照小鼠在感染后4天内死亡，所有用AGP处理的小鼠显示死亡时间延长，并且30%-60%用AGP处理的小鼠存活。在缺乏γ干扰素的小鼠中，AGP的保护作用丧失。长期存活者产生特异性Th1脾细胞反应，特异性抗体以IgG2亚型为主。存活者对雾化的新凶手弗朗西斯菌再次攻击具有完全的抵抗力。因此，预防性给予AGP成功地调节了对雾化新凶手弗朗西斯菌的先天免疫反应，导致对肺土拉菌病的保护性免疫。这是关于TLR配体对新凶手弗朗西斯菌诱导的肺土拉菌病抵抗力的保护作用的首次报道。
