Biphasic and cardiomyocyte-specific IFIT activity protects cardiomyocytes from enteroviral infection
Biphasic and cardiomyocyte-specific IFIT activity protects cardiomyocytes from enteroviral infection
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DOI：
10.1371/journal.ppat.1007674
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发表时间：
2019-04-01
期刊：
影响因子：
6.7
通讯作者：
Whitton, J. Lindsay
中科院分区：
文献类型：
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作者：
Kimura, Taishi;Flynn, Claudia T.;Whitton, J. Lindsay
病毒性心肌炎是一种严重的疾病，通常由B型柯萨奇病毒（CVB）引起。在这里，我们表明，先天性免疫保护CVB3心肌炎需要IFIT（干扰素诱导与tetratricopeptide）的轨迹，这是一个双相的方式。使用IFIT基因座敲除（IFITKO）心肌细胞，我们表明，在IFIT基因座的情况下，病毒复制显着增加，表明组成性IFIT表达抑制CVB在这种细胞类型中的复制。IFN预处理强烈抑制CVB3在野生型（wt）心肌细胞中的复制，但在IFITKO心肌细胞中不抑制，表明其它干扰素刺激的基因（ISG）不能补偿该细胞类型中IFIT的损失。因此，在分离的野生型心肌细胞中，IFIT的抗CVB3活性是双相的，在T1IFN信号传导之前和之后都需要保护。这些体外发现在体内复制。使用新的IFITKO小鼠，我们证明了在感染后数小时内在胰腺、肝脏和心脏中加速的CVB 3复制。IFITKO动物中病毒负荷的这种早期增加加速了几种组织中其他ISG的诱导，增强了病毒从某些组织中的清除，表明与心肌细胞相反，其他ISG可以抵消这些细胞类型的IFIT损失。相反，CVB3在IFITKO心脏中持续存在，并发生心肌炎。因此，心肌细胞有一个特定的，双相的，和近绝对的要求IFIT控制CVB infection.Author摘要病毒可以感染心脏，引起炎症称为心肌炎，这是一个严重的，有时是致命的，疾病。对抗感染的一种方法是刺激我们的免疫系统，鼓励它对抗病毒。然而，目前使用的治疗加速了我们免疫系统的许多不同部分，包括一些在清除病毒方面几乎没有作用的部分，这种广泛的激活增加了潜在有害副作用的风险。我们想确定免疫系统中对抗心脏病毒感染的部分，这样我们就可以通过选择性地只刺激那些免疫反应来改善病毒性心肌炎的治疗，从而保留治疗的益处（即，清除病毒），同时降低其成本（即降低有害副作用的风险）。在本文中，我们证明了一个名为IFIT的蛋白质家族在保护许多组织免受这些感染方面发挥着作用，但在心肌细胞中尤其重要，因为它们是不可或缺的。因此，IFIT代表了治疗病毒性心肌炎的可能靶点。
Viral myocarditis is a serious disease, commonly caused by type B coxsackieviruses (CVB). Here we show that innate immune protection against CVB3 myocarditis requires the IFIT (IFN-induced with tetratricopeptide) locus, which acts in a biphasic manner. Using IFIT locus knockout (IFITKO) cardiomyocytes we show that, in the absence of the IFIT locus, viral replication is dramatically increased, indicating that constitutive IFIT expression suppresses CVB replication in this cell type. IFN pre-treatment strongly suppresses CVB3 replication in wild type (wt) cardiomyocytes, but not in IFITKO cardiomyocytes, indicating that other interferon-stimulated genes (ISGs) cannot compensate for the loss of IFITs in this cell type. Thus, in isolated wt cardiomyocytes, the anti-CVB3 activity of IFITs is biphasic, being required for protection both before and after T1IFN signaling. These in vitro findings are replicated in vivo. Using novel IFITKO mice we demonstrate accelerated CVB3 replication in pancreas, liver and heart in the hours following infection. This early increase in virus load in IFITKO animals accelerates the induction of other ISGs in several tissues, enhancing virus clearance from some tissues, indicating that-in contrast to cardiomyocytes-other ISGs can offset the loss of IFITs from those cell types. In contrast, CVB3 persists in IFITKO hearts, and myocarditis occurs. Thus, cardiomyocytes have a specific, biphasic, and near-absolute requirement for IFITs to control CVB infection.Author summary Viruses can infect the heart, causing inflammation-termed myocarditis-which is a serious, and sometimes fatal, disease. One way to combat the infection is by stimulating our immune system, encouraging it to fight the virus. However, the treatment that is currently used revs up many different parts of our immune system, including some that play little or no role in clearing the virus, and this wide-ranging activation increases the risk of potentially-harmful side effects. We want to identify the parts of the immune system that fight virus infections of the heart, so that we can improve the treatment of viral myocarditis by selectively stimulating only those immune responses, thereby retaining the benefit of treatment (i.e., clearing the virus) while reducing its cost (i.e. lowering the risk of harmful side effects). In this paper, we demonstrate that a family of proteins called IFITs play a role in protecting many tissues against these infections, but are particularly important in heart muscle cells, in which they are indispensable. Thus, IFITs represent a possible target for the treatment of viral myocarditis.