Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier
Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier
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DOI：
10.1172/jci149633
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发表时间：
2021-07-15
影响因子：
15.9
通讯作者：
Fasano, Alessio
中科院分区：
文献类型：
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作者：
Yonker, Lael M.;Gilboa, Tal;Fasano, Alessio
背景在SARS-CoV-2感染或暴露后数周，一些儿童会患上一种严重的、危及生命的疾病，称为儿童多系统炎症综合征（MIS-C）。胃肠道（GI）症状在MIS-C患者中很常见，严重的炎症反应可能导致心脏并发症。MIS-C的原因至今尚未确定。在这里，我们分析了100名儿童的生物标本：19名MIS-C，26名急性COVID-19和55名对照。通过逆转录PCR（RT-PCR）评估粪便中的SARS-CoV-2，并检查血浆中粘膜屏障完整性破坏的标志物，包括zonulin。超灵敏抗原检测用于探测血浆中的SARS-CoV-2抗原血症，并表征免疫应答。作为概念验证，我们用拉唑肽（一种zonulin拮抗剂）治疗MIS-C患者，并监测其对抗原血症的影响和患者的临床反应。我们发现，在患有MIS-C的儿童中，SARS-CoV-2在胃肠道中的长期存在导致了zonulin的释放，zonulin是肠道通透性的生物标志物，随后SARS-CoV-2抗原被运输到血液中，导致炎症过度。MIS-C患者接受拉唑肽治疗后，血浆SARS-CoV-2刺突抗原水平和炎症标志物水平同时下降，临床改善程度高于目前可用的治疗方法。这些关于MIS-C发病机制的机制数据为诊断、治疗和预防MIS-C提供了深入的见解，这是这种日益常见的儿童严重COVID-19相关疾病迫切需要的。
BACKGROUND. Weeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called multisystem inflammatory syndrome in children (MIS-C). Gastrointestinal (GI) symptoms are common in patients with MIS-C, and a severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not been identified to date.METHODS. Here, we analyzed biospecimens from 100 children:19 with MIS-C, 26 with acute COVID-19, and 55 controls. Stools were assessed for SARS-CoV-2 by reverse transcription PCR (RT-PCR), and plasma was examined for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As a proof of concept, we treated a patient with MIS-C with larazotide, a zonulin antagonist, and monitored the effect on antigenemia and the patient's clinical response.RESULTS. We showed that in children with MIS-C, a prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The patient with MIS-C treated with larazotide had a coinciding decrease in plasma SARS-CoV-2 spike antigen levels and inflammatory markers and a resultant clinical improvement above that achieved with currently available treatments.CONCLUSION. These mechanistic data on MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.