SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation
SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation
复制标题
DOI：
10.1101/2020.12.23.424169
复制
发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Lucy G. Thorne;Ann-Kathrin Reuschl;L. Zuliani-Alvarez;M. Whelan;M. Noursadeghi;C. Jolly;G. Towers
中科院分区：
文献类型：
--
作者：
Lucy G. Thorne;Ann-Kathrin Reuschl;L. Zuliani-Alvarez;M. Whelan;M. Noursadeghi;C. Jolly;G. Towers
SARS-CoV-2感染引起广谱免疫病理学疾病，并因炎性共病而加重。需要更好地了解病毒相关炎症的基础机制，以开发有效的治疗方法。在这里，我们发现SARS-CoV-2在肺上皮细胞中快速复制，尽管通过激活细胞质RNA受体RIG-I和MDA 5触发了强大的先天免疫应答。在上皮细胞感染期间产生的炎性介质可以刺激原代人巨噬细胞以增强细胞因子产生并驱动细胞活化。重要的是，这可以通过废除RNA传感或通过抑制下游信号传导途径来限制。当巨噬细胞或上皮细胞受到外源性炎症刺激时，SARS-CoV-2进一步加剧了局部炎症环境。我们提出，肺上皮中SARS-CoV-2的RNA传感是炎症的关键驱动因素，其程度受局部环境的炎症状态的影响，并且特异性抑制先天免疫途径可能有益于减轻炎症相关的COVID-19。研究重点SARS-CoV-2激活肺上皮细胞中的RNA传感器和随后的炎症反应上皮细胞的RNA传感反应驱动促炎性巨噬细胞激活外源性炎症刺激加剧了上皮细胞和巨噬细胞对SARS-CoV-2的反应免疫调节剂抑制RNA传感反应和随后的巨噬细胞炎症图示摘要
SARS-CoV-2 infection causes broad-spectrum immunopathological disease, exacerbated by inflammatory co-morbidities. A better understanding of mechanisms underpinning virus-associated inflammation is required to develop effective therapeutics. Here we discover that SARS-CoV-2 replicates rapidly in lung epithelial cells despite triggering a robust innate immune response through activation of cytoplasmic RNA-ensors RIG-I and MDA5. The inflammatory mediators produced during epithelial cell infection can stimulate primary human macrophages to enhance cytokine production and drive cellular activation. Critically, this can be limited by abrogating RNA sensing, or by inhibiting downstream signalling pathways. SARS-CoV-2 further exacerbates the local inflammatory environment when macrophages or epithelial cells are primed with exogenous inflammatory stimuli. We propose that RNA sensing of SARS-CoV-2 in lung epithelium is a key driver of inflammation, the extent of which is influenced by the inflammatory state of the local environment, and that specific inhibition of innate immune pathways may beneficially mitigate inflammation-associated COVID-19. Highlights SARS-CoV-2 activates RNA sensors and consequent inflammatory responses in lung epithelial cells Epithelial RNA sensing responses drive pro-inflammatory macrophage activation Exogenous inflammatory stimuli exacerbate responses to SARS-CoV-2 in both eplithelial cells and macrophages Immunomodulators inhibit RNA sensing responses and consequent macrophage inflammation Graphical Abstract