J Biol Chem:阻断致命的细胞因子风暴是治疗COVID-19的重要武器

2020-07-26 DAVID K 细胞

杀手不是病毒,而是免疫反应。当前的大流行是独特的,不仅因为它是由一种使每个人都处于危险之中的新病毒引起的,而且还因为先天免疫反应的范围是多样和不可预测的。有的甚至强大到足以致命。

杀手不是病毒,而是免疫反应。当前的大流行是独特的,不仅因为它是由一种使每个人都处于危险之中的新病毒引起的,而且还因为先天免疫反应的范围是多样和不可预测的。有的甚至强大到足以致命。在另一些地区则相对温和。

塔夫斯大学生物医学研究所的Alexander (Sasha) Poltorak的研究与先天免疫有关。先天免疫是一个人对病原体的天生防御,它指示身体的适应性免疫系统产生对抗病毒的抗体。这些抗体反应稍后可用于开发疫苗接种方法。在诺贝尔奖得主Bruce Beutler的实验室里,我与人合着了一篇论文,解释了构成人体先天免疫系统的细胞是如何识别病原体的,以及一般情况下对病原体的过度反应如何可能对宿主有害。在对病毒反应过度的COVID-19患者中尤其如此。

细胞死亡--一场牺牲的棋局

Poltorak研究炎症反应和细胞死亡,这是先天反应的两个主要组成部分。巨噬细胞是一种白细胞,它利用一组传感器来识别病原体,并产生一种叫做细胞因子的蛋白质,这种蛋白质会引发炎症,并向先天免疫系统的其他细胞寻求帮助。此外,巨噬细胞指示适应性免疫系统了解病原体并最终产生抗体。

为了在宿主体内存活,成功的病原体会抑制炎症反应。它们通过阻断巨噬细胞释放细胞因子的能力,并向免疫系统的其他部分发出警报。为了对抗病毒的沉默,被感染的细胞会自杀,或者细胞死亡。虽然在细胞水平上细胞死亡是有害的,但在机体水平上细胞死亡是有益的,因为它阻止了病原体的增殖。

例如,1347年至1351年间,黑死病夺去了欧洲一半人口的生命。黑死病的病原体能够使人们的白细胞失去功能,或使其沉默,并在白细胞中增殖,最终导致个体死亡。然而,在啮齿动物身上,感染的结果却不同。只有受感染的巨噬细胞死亡,从而限制了病原体在啮齿动物体内的扩散,使它们得以存活。

对鼠疫的"沉默"反应与对导致COVID-19的SARS-CoV-2病毒的强烈反应截然不同。这表明,保持先天反应的平衡对COVID-19患者的生存至关重要。

细胞因子风暴之路

下面是免疫系统的过度反应是如何危害人体抵抗感染的。

一些引发炎症的蛋白质被称为趋化因子,它们会警告其他免疫细胞--比如嗜中性粒细胞,这是一种专业的微生物杀手--在感染部位聚集,它们可以最先到达那里并消化病原体。

其他细胞因子--如白细胞介素1b、白细胞介素6和肿瘤坏死因子--引导中性粒细胞从血管进入感染组织。这些细胞因子可以增加心跳,升高体温,触发血液凝块,困住病原体,刺激大脑中的神经元调节体温、发烧、体重减轻和其他生理反应,这些生理反应已经进化到可以杀死病毒。

当这些细胞因子的产生不受控制时,免疫学家将其描述为"细胞因子风暴"。在细胞因子风暴期间,血管进一步扩张(血管化),导致低血压和广泛的血管损伤。风暴引发大量白细胞进入肺部,进而激发更多的免疫细胞,瞄准并杀死受病毒感染的细胞。这场战斗的结果是一堆液体和死细胞,以及随之而来的器官衰竭。

细胞因子风暴是COVID-19病理的核心,对宿主具有毁灭性的后果。

当细胞不能终止炎症反应时,细胞因子的产生使巨噬细胞过度活跃。活化的巨噬细胞破坏骨髓中的干细胞,导致贫血。白细胞介素1b升高可导致发热和器官衰竭。过多的肿瘤坏死因子会导致血管内壁细胞大量死亡,从而导致血管凝结。在某种程度上,风暴变得不可阻挡,不可逆转。

打破细胞因子风暴的药物

治疗COVID的一种策略是部分地基于打破"细胞因子风暴"的恶性循环。这可以通过使用抗体来阻断风暴的主要介质,如IL6或其受体,它存在于身体的所有细胞上。

通过FDA批准的抗体药物如Remicade或Humira或可溶性受体如Enbrel(最初由Bruce Beutler开发)可以抑制肿瘤坏死因子,Enbrel与肿瘤坏死因子结合并防止其触发炎症。肿瘤坏死因子抑制剂的全球市场为220亿美元。

阻断多种细胞因子的药物目前正在进行临床试验,以测试它们是否能有效阻止COVID-19的恶性循环。

原始出处:

Jie Yang 1 2, Hong Zhang 3 2, Weibin Gong 1, et al.S-Glutathionylation of human inducible Hsp70 reveals a regulatory mechanism involving the C-terminal α-helical lid.J Biol Chem. 2020 Jun 12;295(24):8302-8324. doi: 10.1074/jbc.RA119.012372. Epub 2020 Apr 24.

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    2020-10-25 sunylz
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