IRF3-mediated pathogenicity in a murine model of human hepatitis A.
IRF3-mediated pathogenicity in a murine model of human hepatitis A.
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DOI：
10.1371/journal.ppat.1009960
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发表时间：
2021-09
期刊：
影响因子：
6.7
通讯作者：
Lemon SM
中科院分区：
文献类型：
--
作者：
Sun L;Li Y;Misumi I;González-López O;Hensley L;Cullen JM;McGivern DR;Matsuda M;Suzuki R;Sen GC;Hirai-Yuki A;Whitmire JK;Lemon SM
感染甲型肝炎病毒的Ifnar1-/-小鼠概括了人类甲型肝炎的许多基本特征，包括血清丙氨酸氨基转移酶(ALT)升高、肝细胞凋亡和肝脏炎症。先前的研究表明MAVS-IRF3信号与发病机制有关，但IRF3介导的转录与泛素化的IRF3的非转录、促凋亡活性之间的作用尚未解决。在这里，我们使用高通量测序方法比较感染的MAVS-/-和Ifnar1-/-小鼠与未感染的MAVS-/-和Ifnar1/-小鼠的肝内转录，并识别IRF3介导的与肝细胞凋亡和肝脏炎症相关的转录反应。在MAVS-/-小鼠中，感染在转录上是沉默的，在这种情况下，甲型肝炎病毒在肝脏内强劲复制，而不会引起炎症或肝细胞凋亡。相比之下，感染导致Ifnar1/-小鼠数百个基因上调，这些小鼠患上急性肝炎，与人类疾病非常相似。上调的基因包括模式识别受体、干扰素、趋化因子、细胞因子和其他干扰素刺激基因。与Ifnar1-/-小鼠相比，感染IRF3的IRF3由于Ser-388和Ser-390上的丙氨酸替换而转录失活的Irf3S1/S1Ifnar1/-小鼠的肝脏炎症明显减轻，肝细胞几乎没有凋亡。尽管转录组图谱显示在Irf3S1/S1Ifnar1-/-和Ifnar1-/-小鼠中诱导的基因非常相似，但部分基因的表达与肝脏损伤的严重程度有关。其中最突出的是1型和III型干扰素以及以前与细胞凋亡相关的干扰素反应基因，包括ISG12和2‘-5’寡腺苷合成酶家族的多个成员。Ifnl3和Ifnl2转录丰度与疾病严重程度密切相关，但I型和III型干扰素受体双重缺陷的小鼠仍然完全容易受到肝损伤。综上所述，我们的数据表明，在甲型肝炎病毒诱导的小鼠肝损伤中，IRF3介导的转录是必需的，并确定了与致病性相关的关键IRF3反应基因，这与IRF3在酗酒后肝损伤中的转录独立作用有明显的区别。甲型肝炎是一种常见且潜在严重的疾病，由甲型肝炎病毒(HAV)感染引起炎症和肝细胞死亡。这种疾病的发病机制还不完全清楚。在这里，我们描述了在对甲型肝炎的先天性免疫反应中存在各种遗传缺陷的小鼠肝脏RNA转录组的变化。我们证明，这些小鼠与甲型肝炎病毒感染相关的肝损伤是由干扰素调节因子3(IRF3)转录控制下的基因诱导造成的。我们使用高通量RNA测序来确定野生型与转录不全IRF3小鼠中诱导的基因集，排除III型干扰素和IFIT蛋白在疾病发病机制中的作用，并确定与甲型肝炎病毒介导的肝脏病理密切相关的肝内表达的基因。
HAV-infected Ifnar1-/- mice recapitulate many of the cardinal features of hepatitis A in humans, including serum alanine aminotransferase (ALT) elevation, hepatocellular apoptosis, and liver inflammation. Previous studies implicate MAVS-IRF3 signaling in pathogenesis, but leave unresolved the role of IRF3-mediated transcription versus the non-transcriptional, pro-apoptotic activity of ubiquitylated IRF3. Here, we compare the intrahepatic transcriptomes of infected versus naïve Mavs-/- and Ifnar1-/- mice using high-throughput sequencing, and identify IRF3-mediated transcriptional responses associated with hepatocyte apoptosis and liver inflammation. Infection was transcriptionally silent in Mavs-/- mice, in which HAV replicates robustly within the liver without inducing inflammation or hepatocellular apoptosis. By contrast, infection resulted in the upregulation of hundreds of genes in Ifnar1-/- mice that develop acute hepatitis closely modeling human disease. Upregulated genes included pattern recognition receptors, interferons, chemokines, cytokines and other interferon-stimulated genes. Compared with Ifnar1-/- mice, HAV-induced inflammation was markedly attenuated and there were few apoptotic hepatocytes in livers of infected Irf3S1/S1Ifnar1-/- mice in which IRF3 is transcriptionally-inactive due to alanine substitutions at Ser-388 and Ser-390. Although transcriptome profiling revealed remarkably similar sets of genes induced in Irf3S1/S1Ifnar1-/- and Ifnar1-/- mice, a subset of genes was differentially expressed in relation to the severity of the liver injury. Prominent among these were both type 1 and type III interferons and interferon-responsive genes associated previously with apoptosis, including multiple members of the ISG12 and 2’-5’ oligoadenylate synthetase families. Ifnl3 and Ifnl2 transcript abundance correlated strongly with disease severity, but mice with dual type 1 and type III interferon receptor deficiency remained fully susceptible to liver injury. Collectively, our data show that IRF3-mediated transcription is required for HAV-induced liver injury in mice and identify key IRF3-responsive genes associated with pathogenicity, providing a clear distinction from the transcription-independent role of IRF3 in liver injury following binge exposure to alcohol. Hepatitis A is a common and potentially serious disease involving inflammation and liver cell death resulting from infection with the picornavirus, hepatitis A virus (HAV). The pathogenesis of the disease is incompletely understood. Here, we have profiled changes in the RNA transcriptome of livers from mice with various genetic deficiencies in the innate immune response to HAV. We show that the liver injury associated with HAV infection in these mice results from the induction of genes under transcriptional control of interferon regulatory factor 3 (IRF3). We use high-throughput RNA sequencing to identify sets of genes induced in mice with wild-type versus transcriptionally-incompetent IRF3, rule out roles for type III interferons and IFIT proteins in disease pathogenesis, and identify genes with intrahepatic expression correlating closely with HAV-mediated liver pathology.
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影响因子：
6.4
作者：
Hirai-Yuki A;Hensley L;Whitmire JK;Lemon SM
通讯作者：
Lemon SM
影响因子：
6.7
作者：
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Whitton, J. Lindsay
影响因子：
5.4
作者：
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通讯作者：
Lemon, Stanley M.
影响因子：
32.4
作者：
Kim, Jihye;Chang, Dong-Yeop;Shin, Eui-Cheol
通讯作者：
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影响因子：
25.7
作者：
Misumi I;Mitchell JE;Lund MM;Cullen JM;Lemon SM;Whitmire JK
通讯作者：
Whitmire JK