Table_7_Defining the Innate Immune Responses for SARS-CoV-2-Human Macrophage Interactions.xls

Host innate immune response follows severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and it is the driver of the acute respiratory distress syndrome (ARDS) amongst other inflammatory end-organ morbidities. Such life-threatening coronavirus disease 2019 (COVID-19) is heralded by virus-induced activation of mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells). MPs play substantial roles in aberrant immune secretory activities affecting profound systemic inflammation and end-organ malfunctions. All follow the presence of persistent viral components and virions without evidence of viral replication. To elucidate SARS-CoV-2-MP interactions we investigated transcriptomic and proteomic profiles of human monocyte-derived macrophages. While expression of the SARS-CoV-2 receptor, the angiotensin-converting enzyme 2, paralleled monocyte-macrophage differentiation, it failed to affect productive viral infection. In contrast, simple macrophage viral exposure led to robust pro-inflammatory cytokine and chemokine expression but attenuated type I interferon (IFN) activity. Both paralleled dysregulation of innate immune signaling pathways, specifically those linked to IFN. We conclude that the SARS-CoV-2-infected host mounts a robust innate immune response characterized by a pro-inflammatory storm heralding end-organ tissue damage.

宿主固有免疫应答在严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）感染后被激活，其是引发急性呼吸窘迫综合征（ARDS）及其他炎症性终末器官病变的关键诱因。危及生命的新型冠状病毒肺炎（COVID-19）以病毒诱导的单核吞噬细胞（MPs；单核细胞、巨噬细胞与树突状细胞）激活为显著特征。单核吞噬细胞在异常免疫分泌活动中发挥关键作用，可介导严重的全身性炎症与终末器官功能障碍，而上述所有病理过程均伴随持续存在的病毒组分与病毒粒子，但未检测到病毒复制的证据。为阐明SARS-CoV-2与单核吞噬细胞的相互作用机制，我们对人单核细胞衍生的巨噬细胞开展了转录组与蛋白质组学分析。尽管SARS-CoV-2的受体——血管紧张素转换酶2（ACE2）的表达水平与单核细胞向巨噬细胞的分化进程同步，但该受体并未介导产毒性病毒感染。与之相反，仅通过简单的巨噬细胞病毒暴露即可诱导强烈的促炎细胞因子与趋化因子表达，但会减弱I型干扰素（IFN）的活性。上述两种现象均与固有免疫信号通路（尤其是与干扰素相关的通路）的失调密切相关。本研究最终得出结论：感染SARS-CoV-2的宿主会启动强烈的固有免疫应答，其核心特征为促炎风暴，进而引发终末器官组织损伤。