Mononuclear phagocyte differentiation trajectories driving a cytokine storm and tissue damage in COVID-19 (B09*)

SARS-CoV-2感染中细胞因子风暴的原因尚不清楚，但严重的COVID-19与骨髓细胞失调有关，这表明单核吞噬细胞是重要的参与者。我们之前在流感小鼠模型和感染的类器官中研究了巨噬细胞向促炎性和抗炎性巨噬细胞的分化，并确定了I型干扰素是病毒性肺炎（SH组）肺组织损伤的主要驱动因素。此外，我们最近在狼疮易感小鼠（AT组）中发现了高水平I型干扰素诱导的巨噬细胞激活综合征的驱动因素。在这里，我们建议利用我们目前对导致巨噬细胞过度激活的途径的理解来确定驱动COVID-19细胞因子风暴的途径。我们的目标是开始阐明COVID-19中单核吞噬细胞过度活化、肺泡损伤和内皮功能障碍的机制基础。

The cause of a cytokine storm in SARS-CoV-2 infection is unclear but severe COVID-19 is associated with myeloid cell dysregulation, indicating mononuclear phagocytes are important players. We have previously studied macrophage differentiation towards pro- versus anti-inflammatory macrophages in mouse models of influenza and in infected organoids and identified type I interferons as major drivers of lung tissue injury in viral pneumonia (SH group). We furthermore recently identified drivers of a macrophage activation syndrome induced by high levels of type I interferons in lupus-prone mice (AT group). Here we propose to employ our current understanding of the pathways leading to macrophage hyperactivation to identify pathways driving a cytokine storm in COVID-19. Our goal is to begin to shed light to the mechanistic underpinnings of mononuclear phagocyte hyperactivation, alveolar damage and endothelial dysfunction in COVID-19.