Division of Pulmonary and Critical Care Medicine, Oregon Health and Sciences University, Portland, Oregon, United States of America.
PLoS One. 2007 Aug 15;2(8):e736. doi: 10.1371/journal.pone.0000736.
Bacillus anthracis, the etiologic agent of inhalational anthrax, is a facultative intracellular pathogen. Despite appropriate antimicrobial therapy, the mortality from inhalational anthrax approaches 45%, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Type I and Type II Interferons (IFN) are prominent members of the host innate immune response and are required for control of intracellular pathogens. We have previously described a protective role for exogenous Type I and Type II IFNs in attenuating intracellular B.anthracis germination and macrophage cell death in vitro.
We sought to extend these findings in an in vivo model of inhalational anthrax, utilizing the Sterne strain (34F2) of B.anthracis. Mice devoid of STAT1, a component of IFN-alpha and IFN-gamma signaling, had a trend towards increased mortality, bacterial germination and extrapulmonary spread of B.anthracis at 24 hrs. This was associated with impaired IL-6, IL-10 and IL-12 production. However, administration of exogenous IFN-gamma, and to a lesser extent IFN-alpha, at the time of infection, markedly increased lethality. While IFNs were able to reduce the fraction of germinated spores within the lung, they increased both the local and systemic inflammatory response manifest by increases in IL-12 and reductions in IL-10. This was associated with an increase in extrapulmonary dissemination. The mechanism of IFN mediated inflammation appears to be in part due to STAT1 independent signaling.
In conclusion, while endogenous IFNs are essential for control of B.anthracis germination and lethality, administration of exogenous IFNs appear to increase the local inflammatory response, thereby increasing mortality.
炭疽杆菌是吸入性炭疽的病原体，是一种兼性细胞内病原体。尽管进行了适当的抗菌治疗，吸入性炭疽的死亡率仍接近 45%，这突显了需要更好的辅助治疗方法。从暴露到发病的潜伏期不同，表明宿主固有免疫反应起着重要作用。I 型和 II 型干扰素（IFN）是宿主固有免疫反应的突出成员，是控制细胞内病原体所必需的。我们之前描述了外源性 I 型和 II 型 IFN 在体外减轻细胞内炭疽杆菌发芽和巨噬细胞细胞死亡中的保护作用。
我们试图在吸入性炭疽的体内模型中扩展这些发现，利用炭疽杆菌 Sterne 株（34F2）。缺乏 IFN-α和 IFN-γ信号传导组件 STAT1 的小鼠在 24 小时时死亡率、炭疽杆菌发芽和肺外传播呈增加趋势。这与 IL-6、IL-10 和 IL-12 产生受损有关。然而，在感染时给予外源性 IFN-γ，并且在较小程度上 IFN-α，大大增加了致死率。虽然 IFNs 能够减少肺部内发芽孢子的比例，但它们增加了局部和全身炎症反应，表现为 IL-12 增加和 IL-10 减少。这与肺外传播的增加有关。IFN 介导的炎症的机制部分似乎是由于 STAT1 独立的信号传导。
总之，虽然内源性 IFNs 对于控制炭疽杆菌的发芽和致死至关重要，但外源性 IFNs 的给予似乎会增加局部炎症反应，从而增加死亡率。
