Exogenous gamma and alpha/beta interferon rescues human macrophages from cell death induced by Bacillus anthracis
Exogenous gamma and alpha/beta interferon rescues human macrophages from cell death induced by Bacillus anthracis
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DOI：
10.1128/iai.72.3.1291-1297.2004
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发表时间：
2004-03-01
影响因子：
3.1
通讯作者：
Weiden, MD
中科院分区：
文献类型：
--
作者：
Gold, JA;Hoshino, Y;Weiden, MD
在最近的生物恐怖主义相关的爆发，吸入性炭疽有45%的死亡率，尽管适当的抗菌治疗，强调需要更好的辅助治疗。暴露和疾病发展之间的可变潜伏期表明宿主的先天免疫应答起着重要作用。肺泡巨噬细胞可能是暴露于吸入性炭疽的第一个免疫细胞，这些细胞的干扰素（IFN）应答包括宿主对炭疽杆菌胞内感染的先天免疫应答的重要分支。此外，IFN已被用作治疗另一种细胞内病原体结核分枝杆菌的免疫佐剂。我们建立了一个B模型。炭疽感染Sterne菌株（34 F（2）），其中含有致命毒素（LeTx）。34 F（2）对小鼠和人巨噬细胞具有致死性。用IFN处理显著提高细胞活力并减少萌发的细胞内孢子的数量。感染34 F（2）不能诱导潜在的转录因子信号转导和转录激活因子1（STAT 1）和ISGF-3，这是IFN应答的核心。此外，34 F（2）降低了STAT 1对外源性α/β IFN的激活，表明直接抑制IFN信号传导。尽管34 F（2）有LeTx，但没有丝裂原活化蛋白激酶激酶3裂解，p38被正常诱导，这表明B的这些早期效应。巨噬细胞中的炭疽感染不依赖于LeTx。这些数据表明两种IFN在控制B中的重要作用。炭疽和使用外源性IFN作为免疫辅助治疗的潜在益处。
During the recent bioterrorism-related outbreaks, inhalational anthrax had a 45% mortality in spite of appropriate antimicrobial therapy, 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. Alveolar macrophages are likely the first immune cells exposed to inhalational anthrax, and the interferon (IFN) response of these cells comprises an important arm of the host innate immune response to intracellular infection with Bacillus anthracis. Furthermore, IFNs have been used as immunoadjuvants for treatment of another intracellular pathogen, Mycobacterium tuberculosis. We established a model of B. anthracis infection with the Sterne strain (34F(2)) which contains lethal toxin (LeTx). 34F(2) was lethal to murine and human macrophages. Treatment with IFNs significantly improved cell viability and reduced the number of germinated intracellular spores. Infection with 34F(2) failed to induce the latent transcription factors signal transducer and activators of transcription 1 (STAT1) and ISGF-3, which are central to the IFN response. Furthermore, 34F(2) reduced STAT1 activation in response to exogenous alpha/beta IFN, suggesting direct inhibition of IFN signaling. Even though 34F(2) has LeTx, there was no mitogen-activated protein kinase kinase 3 cleavage and p38 was normally induced, suggesting that these early effects of B. anthracis infection in macrophages are independent of LeTx. These data suggest an important role for both IFNs in the control of B. anthracis and the potential benefit of using exogenous IFN as an immunoadjuvant therapy.