Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas 77555-0436, USA.
Infect Immun. 2010 Apr;78(4):1700-10. doi: 10.1128/IAI.00736-09. Epub 2010 Feb 1.
We investigated whether Toll-like receptor 3 (TLR3) stimulation would protect the host from inhaled Francisella tularensis. TLR3 is expressed by respiratory epithelial cells and macrophages and can be activated by a synthetic double-stranded RNA ligand called polyinosine-polycytosine [poly(I:C)]. Thus, we evaluated poly(I:C) as a novel treatment against inhaled F. tularensis. In vivo, BALB/c mice intranasally (i.n.) treated with poly(I:C) (100 microg/mouse) 1 h before or after Schu 4 or LVS (100 CFU) i.n. challenge showed that poly(I:C) treatment significantly reduced bacterial load in the lungs (P < 0.05). Bronchoalveolar lavage from poly(I:C)-treated mice alone or combined with F. tularensis infection significantly increased cytokine secretion and enhanced neutrophil influx to lung tissues. Poly(I:C) responses were transient but significantly prolonged the survival of treated mice after i.n. F. tularensis challenge relative to mock treated animals. This prolonged survival providing a longer window for initiation of levofloxacin (LEVO) treatment (40 mg/kg). Animals treated with poly(I:C), challenged with F. tularensis, and then treated with LEVO 5 days later had 100% survival relative to 0% survival in animals receiving LEVO alone. Mechanistically, poly(I:C) given to human monocyte-derived macrophages before or after Schu 4 or LVS challenge (multiplicity of infection, 20:1) had significantly reduced intracellular bacterial replication (P < 0.05). These data suggest that poly(I:C) may represent a potential therapeutic agent against inhaled F. tularensis that prolongs survival and the opportunity to initiate standard antibiotic therapy (i.e., LEVO).
我们研究了 Toll 样受体 3（TLR3）刺激是否会保护宿主免受吸入性弗朗西斯氏菌的侵害。TLR3 由呼吸道上皮细胞和巨噬细胞表达，可被一种称为聚肌苷酸-聚胞苷酸（poly[I:C]）的合成双链 RNA 配体激活。因此，我们评估了 poly[I:C]作为一种新型治疗吸入性弗朗西斯氏菌的方法。在体内，BALB/c 小鼠在 Schu 4 或 LVS（100 CFU）经鼻挑战前 1 小时或后 1 小时用 poly[I:C]（100 μg/只）经鼻处理，结果表明 poly[I:C]处理可显著降低肺部的细菌负荷（P<0.05）。单独用 poly[I:C]或联合感染弗朗西斯氏菌处理的小鼠的支气管肺泡灌洗液显著增加细胞因子分泌并增强中性粒细胞向肺组织的浸润。poly[I:C]反应是短暂的，但可显著延长经鼻感染弗朗西斯氏菌后接受治疗的小鼠的存活时间，相对于模拟治疗的动物。这种延长的存活为开始左氧氟沙星（LEVO）治疗（40 mg/kg）提供了更长的时间窗口。用 poly[I:C]处理、用弗朗西斯氏菌挑战然后在 5 天后用 LEVO 治疗的动物的存活率为 100%，而单独接受 LEVO 的动物的存活率为 0%。从机制上讲，在 Schu 4 或 LVS 挑战前或后给予人单核细胞衍生的巨噬细胞 poly[I:C]（感染复数，20:1）可显著减少细胞内细菌复制（P<0.05）。这些数据表明，poly[I:C]可能代表一种有潜力的治疗吸入性弗朗西斯氏菌的方法，可延长存活时间并为开始标准抗生素治疗（即 LEVO）提供机会。
