SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation.
SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation.
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DOI：
10.1126/sciimmunol.abg0833
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发表时间：
2021-04-07
影响因子：
24.8
通讯作者：
Kazemian M
中科院分区：
文献类型：
--
作者：
Yan B;Freiwald T;Chauss D;Wang L;West E;Mirabelli C;Zhang CJ;Nichols EM;Malik N;Gregory R;Bantscheff M;Ghidelli-Disse S;Kolev M;Frum T;Spence JR;Sexton JZ;Alysandratos KD;Kotton DN;Pittaluga S;Bibby J;Niyonzima N;Olson MR;Kordasti S;Portilla D;Wobus CE;Laurence A;Lionakis MS;Kemper C;Afzali B;Kazemian M
SARS-CoV-2 通过细胞固有的旁路途径转化酶诱导 JAK-STAT1 依赖性补体 C3 转录和加工。 2019 年冠状病毒病 (COVID-19) 患者会出现多种影响肺、肝、肾和肠道的急性临床表现。血管紧张素转换酶 (ACE) 2 是致病病毒 SARS-CoV-2 的最佳特征进入受体，在上述组织中高度表达。然而，人们对该疾病的发病机制仍知之甚少。在这里，我们意外地发现补体系统是肺上皮细胞中 SARS-CoV-2 感染最强烈诱导的细胞内途径之一。 SARS-CoV-2 感染呼吸道上皮细胞会产生激活的补体成分 C3a，并且可以被补体因子 B 的细胞渗透性抑制剂 (CFBi) 阻断，表明呼吸道上皮细胞中存在诱导型细胞固有的 C3 转化酶。在患者支气管肺泡灌洗液的细胞内，骨髓细胞、淋巴细胞和上皮细胞中补体激活的独特特征与疾病的严重程度相关。 SARS-CoV-2 诱导的基因以及可以使这些基因正常化的药物都表明干扰素-JAK1/2-STAT1 信号系统和 NF-B 是其表达的主要驱动因素。 Ruxolitinib 是一种 JAK1/2 抑制剂，可使肺上皮细胞系中 SARS-CoV-2 诱导的干扰素特征基因和所有补体基因转录物正常化，但不影响 NF-B 调节基因。鲁索替尼单独或与抗病毒药物瑞德西韦联合使用，可抑制受感染细胞产生的 C3a 蛋白。总之，我们假设 JAK 抑制剂和使 NF-B 信号转导正常化的药物的联合治疗可能会在重症 COVID-19 的临床应用中发挥作用。
SARS-CoV-2 induces JAK-STAT1dependent complement C3 transcription and processing by a cell-intrinsic alternative pathway convertase. Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys and gut. Angiotensin converting enzyme (ACE) 2, the best-characterized entry receptor for the disease-causing virus SARS-CoV-2, is highly expressed in the aforementioned tissues. However, the pathways that underlie the disease are still poorly understood. Here, we unexpectedly found that the complement system was one of the intracellular pathways most highly induced by SARS-CoV-2 infection in lung epithelial cells. Infection of respiratory epithelial cells with SARS-CoV-2 generated activated complement component C3a and could be blocked by a cell-permeable inhibitor of complement factor B (CFBi), indicating the presence of an inducible cell-intrinsic C3 convertase in respiratory epithelial cells. Within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid and epithelial cells tracked with disease severity. Genes induced by SARS-CoV-2 and the drugs that could normalize these genes both implicated the interferon-JAK1/2-STAT1 signaling system and NF-B as the main drivers of their expression. Ruxolitinib, a JAK1/2 inhibitor, normalized interferon signature genes and all complement gene transcripts induced by SARS-CoV-2 in lung epithelial cell lines, but did not affect NF-B-regulated genes. Ruxolitinib, alone or in combination with the antiviral remdesivir, inhibited C3a protein produced by infected cells. Together, we postulate that combination therapy with JAK inhibitors and drugs that normalize NF-B-signaling could potentially have clinical application for severe COVID-19.
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影响因子：
64.8
作者：
Carvelli, Julien;Demaria, Olivier;Vivier, Eric
通讯作者：
Vivier, Eric
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DOI：
10.1126/science.aad1210
发表时间：
2016-06-17
期刊：
Science (New York, N.Y.)
影响因子：
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16.8
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影响因子：
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作者：
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作者：
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