The SARS-CoV-2 E protein induces Toll-like receptor 2-mediated neonatal lung injury in a model of COVID-19 viremia that is rescued by the glucocorticoid ciclesonide.
The SARS-CoV-2 E protein induces Toll-like receptor 2-mediated neonatal lung injury in a model of COVID-19 viremia that is rescued by the glucocorticoid ciclesonide.
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SARS-CoV-2 E 蛋白在 COVID-19 病毒血症模型中诱导 Toll 样受体 2 介导的新生儿肺损伤，而糖皮质激素环索奈德可挽救该模型。
DOI：
10.1152/ajplung.00410.2022
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Sampath,Venkatesh
中科院分区：
文献类型：
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作者：
Menden,HeatherL;Mabry,SherryM;Venkatraman,Aparna;Xia,Sheng;DeFranco,DonaldB;Yu,Wei;Sampath,Venkatesh
SARS-CoV-2病毒血症与儿童和成人的急性肺损伤(ALI)和死亡率增加有关。循环中的病毒成分介导新冠肺炎ALI的机制尚不清楚。在新生新冠肺炎模型中，我们验证了SARS-CoV-2包膜蛋白诱导Toll样受体介导的ALI和肺重塑的假说。新生C57BL6小鼠经腹腔注射E蛋白后，肺细胞因子[白介素6、肿瘤坏死因子α和白介素1β(IL1β)]和典型的促炎因子受体信号呈剂量依赖性增加。系统E蛋白诱导的内皮免疫激活、免疫细胞内流、转化生长因子β信号转导和肺基质重塑抑制了发育中肺的肺泡化。E蛋白介导的ALI和转化生长因子ββ信号在Tlr2−/−小鼠中受到抑制，但在Tlr4−/−小鼠中不受抑制。单次注射E蛋白可诱导慢性肺泡重塑，表现为放射状肺泡计数减少和平均线形截距增加。环索奈德是一种人工合成的糖皮质激素，可抑制E蛋白诱导的促炎TLR信号转导和ALI。在体外，E蛋白介导的炎症和细胞死亡依赖于TLR2，并被环索奈德所拯救。本研究旨在探讨SARS-CoV-2病毒血症患儿ALI和肺泡重塑的发病机制，同时揭示类固醇激素的疗效。新发现，SARS-CoV-2包膜蛋白通过激活Toll样受体介导急性肺损伤(ALI)和肺泡重塑，而糖皮质激素环索奈德可挽救ALI和肺泡重构。
SARS-CoV-2 viremia is associated with increased acute lung injury (ALI) and mortality in children and adults. The mechanisms by which viral components in the circulation mediate ALI in COVID-19 remain unclear. We tested the hypothesis that the SARS-CoV-2 envelope (E) protein induces Toll-like receptor (TLR)-mediated ALI and lung remodeling in a model of neonatal COVID-19. Neonatal C57BL6 mice given intraperitoneal E protein injections revealed a dose-dependent increase in lung cytokines [interleukin 6 (Il6), tumor necrosis factor (Tnfα), and interleukin 1 beta (Il1β)] and canonical proinflammatory TLR signaling. Systemic E protein induced endothelial immune activation, immune cell influx, and TGFβ signaling and lung matrix remodeling inhibited alveolarization in the developing lung. E protein-mediated ALI and transforming growth factor beta (TGFβ) signaling was repressed inTlr2−/−, but notTlr4−/−mice. A single dose of intraperitoneal E protein injection induced chronic alveolar remodeling as evidenced by a decrease in radial alveolar counts and increase in mean linear intercepts. Ciclesonide, a synthetic glucocorticoid, inhibited E protein-induced proinflammatory TLR signaling and ALI. In vitro, E protein-mediated inflammation and cell death were TLR2-dependent in human primary neonatal lung endothelial cells and were rescued by ciclesonide. This study provides insight into the pathogenesis of ALI and alveolar remodeling with SARS-CoV-2 viremia in children, whereas revealing the efficacy of steroids.NEW & NOTEWORTHYWe reveal that the envelope protein of SARS-CoV-2 mediates acute lung injury (ALI) and alveolar remodeling through Toll-like receptor activation, which is rescued by the glucocorticoid, ciclesonide.