Pharmacologic Activation of the Innate Immune System to Prevent Respiratory Viral Infections
Pharmacologic Activation of the Innate Immune System to Prevent Respiratory Viral Infections
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DOI：
10.1165/rcmb.2010-0288oc
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发表时间：
2011-09-01
影响因子：
6.4
通讯作者：
Albelda, Steven M.
中科院分区：
文献类型：
--
作者：
Cheng, Guanjun;Wang, Liang-Chuan S.;Albelda, Steven M.
需要能够迅速抑制流感或其他呼吸道病原体引起的呼吸道感染的药物。一种方法是利用原发性先天免疫防御来对抗病毒感染，例如激活IFN通路。在这项研究中，我们报道了一种名为5,6-二甲基黄酮-4-乙酸（DMXAA）的小细胞可渗透化合物在体外和体内通过先天免疫激活诱导对水疱性口炎病毒和甲型H1N1流感病毒的保护。通过小鼠C10支气管上皮细胞系和鼻上皮细胞的原代培养，我们证明DMXAA激活IFN调节因子-3通路，导致IFN- β的产生，并随后高水平诱导IFN- β依赖蛋白，如黏液病毒抗性1 （Mx1）和2',5'-低聚腺苷酸合成酶1 （OAS1）。经鼻DMXAA处理的小鼠鼻黏膜、气管和肺中Mx1和OAS1 mRNA/蛋白表达升高。当鼻内注射致死剂量的甲型H1N1流感病毒时，DMXAA降低了肺部的病毒滴度，保护80%的小鼠免于死亡，即使在感染前24小时注射也是如此。这些数据表明，DMXAA等可以直接激活呼吸道上皮细胞中的先天免疫途径（如IFN调节因子-3/IFN- β系统）的药物可用于预防流感肺炎和其他呼吸道病毒感染。这种方法在人类身上的发展对于在病毒大流行或生物恐怖袭击的早期阶段保护卫生保健专业人员和“第一响应者”可能很有价值。
Drugs that can rapidly inhibit respiratory infection from influenza or other respiratory pathogens are needed. One approach is to engage primary innate immune defenses against viral infection, such as activating the IFN pathway. In this study, we report that a small, cell-permeable compoundcalled 5,6-di-methylxanthenone-4-acetic acid (DMXAA) can induce protection against vesicular stomatitis virus in vitro and H1N1 influenza A virus in vitro and in vivo through innate immuneactivation. Using the mouse C10 bronchial epithelial cell line and primary cultures of nasal epithelial cells, we demonstrate DMXAA activates the IFN regulatory factor-3 pathway leading to production of IFN-beta and subsequent high-level induction of IFN-beta-dependent proteins, such as myxovirus resistance 1 (Mx1) and 2',5'-oligoadenylate synthetase 1 (OAS1). Mice treated with DMXAA intranasally elevate mRNA/protein expression of Mx1 and OAS1 in the nasal mucosa, trachea, and lung. When challenged intranasally with a lethal dose of H1N1 influenza A virus, DMXAA reduced viral titers in the lungs and protected 80% of mice from death, even when given at 24 hours before infection. These data show that agents, like DMXAA, that can directly activate innate immune pathways, such as the IFN regulatory factor-3/IFN-beta system, in respiratory epithelial cells can be used to protect from influenza pneumonia and potentially in other respiratory viral infections. Development of this approach in humans could be valuable for protecting health care professionals and "first responders" in the early stages of viral pandemics or bioterror attacks.