Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population
Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population
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DOI：
10.1172/jci40817
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发表时间：
2010-05-01
影响因子：
15.9
通讯作者：
Sher, Alan
中科院分区：
文献类型：
--
作者：
Antonelli, Lis R. V.;Rothfuchs, Antonio Gigliotti;Sher, Alan
已证明I型IFN对细菌感染的结果具有主要调节作用。为了评估外源性诱导的I型IFN对结核分枝杆菌感染结果的影响，我们用聚肌苷酸-聚胞苷酸与聚-L-赖氨酸和羧甲基纤维素缩合（聚-ICLC），一种旨在刺激长时间高水平产生I型IFN的药物鼻内治疗病原体暴露小鼠。药物治疗，M。结核病感染的WT小鼠，而不是缺乏IFN-α β受体1（IFN α β R;也称为IFNAR 1）的小鼠，显示出肺杆菌负荷的显著升高，伴随着广泛的肺坏死，而没有可检测到的Th 1效应功能的损害。重要的是，来自Poly-ICLC处理的M.结核病感染的小鼠表现出CD 11b（+）F4/80（+）Gr 1（int）细胞的显著增加，相对于从感染的未治疗的对照组中纯化的相同细胞亚群，这些细胞表现出降低的MHC II表达和增强的细菌水平。此外，Poly-ICLC触发的CD 11b（+）F4/80（+）Gr 1（int）群体的肺部募集和伴随的感染加重均与I型IFN诱导的趋化因子编码基因Ccl 2上调相关，并依赖于趋化因子受体CCR 2的宿主表达。上述结果表明，Poly-ICLC治疗可对M的结局产生不良影响。结核感染，通过促进肺中允许的骨髓细胞群的积累。此外，这些数据表明，药物刺激I型干扰素应谨慎使用暴露于这种病原体的患者。
Type I IFN has been demonstrated to have major regulatory effects on the outcome of bacterial infections. To assess the effects of exogenously induced type I IFN on the outcome of Mycobacterium tuberculosis infection, we treated pathogen-exposed mice intranasally with polyinosinic-polycytidylic acid condensed with poly-L-lysine and carboxymethylcellulose (Poly-ICLC), an agent designed to stimulate prolonged, high-level production of type I IFN. Drug-treated, M. tuberculosis-infected WT mice, but not mice lacking IFN-alpha beta receptor 1 (IFN alpha beta R; also known as IFNAR1), displayed marked elevations in lung bacillary loads, accompanied by widespread pulmonary necrosis without detectable impairment of Th1 effector function. Importantly, lungs from Poly-ICLC-treated M. tuberculosis-infected mice exhibited a striking increase in CD11b(+)F4/80(+)Gr1(int) cells that displayed decreased MHC II expression and enhanced bacterial levels relative to the same subset of cells purified from infected, untreated controls. Moreover, both the Poly-ICLC-triggered pulmonary recruitment of the CD11b(+)F4/80(+)Gr1(int) population and the accompanying exacerbation of infection correlated with type I IFN-induced upregulation of the chemokine-encoding gene Ccl2 and were dependent on host expression of the chemokine receptor CCR2. The above findings suggest that Poly-ICLC treatment can detrimentally affect the outcome of M. tuberculosis infection, by promoting the accumulation of a permissive myeloid population in the lung. In addition, these data suggest that agents that stimulate type I IFN should be used with caution in patients exposed to this pathogen.