Relative contribution of IL-1α, IL-1β and TNF to the host response to Mycobacterium tuberculosis and attenuated M. bovis BCG
Relative contribution of IL-1α, IL-1β and TNF to the host response to Mycobacterium tuberculosis and attenuated M. bovis BCG
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DOI：
10.1002/iid3.9
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发表时间：
2013-10-01
影响因子：
3.2
通讯作者：
Quesniaux, Valerie F. J.
中科院分区：
文献类型：
--
作者：
Bourigault, Marie-Laure;Segueni, Noria;Quesniaux, Valerie F. J.
TNF和IL-1是严重炎性疾病中涉及的主要介质，针对它们开发了治疗性中和抗体。然而，TNF和IL-1受体途径对于结核分枝杆菌感染的控制是必不可少的，并且评估IL-1 α、IL-1 β和TNF各自的作用是至关重要的。使用基因靶向小鼠，我们表明，缺乏IL-1 α和IL-1 β重演了不受控制的M。在IL-1 R1缺陷型小鼠中观察到，结核感染伴随细菌负荷增加、肺部炎症加重、IFNg升高、IL-23 p19降低和快速死亡。然而，在单一缺陷小鼠中IL-1 α或IL-1 β的存在足以控制急性M。在TNF缺陷小鼠在4周内死于压倒性感染的条件下，全身感染减毒支原体。在没有功能性IL-1通路的情况下，牛BCG被控制，但在没有TNF的情况下不被控制。因此，尽管IL-1 α和IL-1 β都是宿主对强毒M.在结核病中，IL-1 α或IL-1 β的存在允许对急性M. IL-1途径是控制结核分枝杆菌感染的重要途径。牛卡介苗急性感染。这与TNF形成鲜明对比，TNF是宿主对减毒和毒性分枝杆菌的反应所必需的，并且可能对IL-1b中和抗体的抗炎治疗有影响。
TNF and IL-1 are major mediators involved in severe inflammatory diseases against which therapeutic neutralizing antibodies are developed. However, both TNF and IL-1 receptor pathways are essential for the control of Mycobacterium tuberculosis infection, and it is critical to assess the respective role of IL-1 alpha, IL-1 beta, and TNF. Using gene-targeted mice we show that absence of both IL-1 alpha and IL-1 beta recapitulates the uncontrolled M. tuberculosis infection with increased bacterial burden, exacerbated lung inflammation, high IFNg, reduced IL-23 p19 and rapid death seen in IL-1R1-deficient mice. However, presence of either IL-1 alpha or IL-1 beta in single-deficient mice is sufficient to control acute M. tuberculosis infection, with restrained bacterial burden and lung pathology, in conditions where TNF deficient mice succumbed within 4 weeks with overwhelming infection. Systemic infection by attenuated M. bovis BCG was controlled in the absence of functional IL-1 pathway, but not in the absence of TNF. Therefore, although both IL-1 alpha and IL-1 beta are required for a full host response to virulent M. tuberculosis, the presence of either IL-1 alpha or IL-1 beta allows some control of acute M. tuberculosis infection, and IL-1 pathway is dispensable for controlling M. bovis BCG acute infection. This is in sharp contrast with TNF, which is essential for host response to both attenuated and virulent mycobacteria and may have implications for anti-inflammatory therapy with IL-1b neutralizing antibodies.