An Immune Cell Atlas Reveals Dynamic COVID-19 Specific Neutrophil Programming Amendable to Therapy

SARS-CoV-2 is a novel coronavirus that causes acute respiratory distress syndrome (ARDS) and death. Innate immune cells are critical for host defense but are also the primary drivers of acute respiratory distress syndrome. The relationships between innate cellular responses in ARDS resulting from COVID-19 compared to other causes of ARDS, such as bacterial sepsis is unclear. Moreover, the beneficial cellular effects of dexamethasone therapy during severe COVID-19 remains speculative but understanding their mechanistic effects could improve rationally targeted drug design. We discovered that compared to bacterial septic ARDS, COVID-19 induced distinct neutrophil polarization characterized by either interferon (IFN) or prostaglandin (PG) active states. IFN polarization required the transcriptional regulators PRDM1, STAT1 and IRF1 while prostaglandin polarization was induced by E2F4. Bacterial ARDS neutrophils upregulated antibacterial molecules such as PLAC8 via STAT5b and demonstrated conventional transcription factors CEBPA and CEBPB. Steroid therapy rapidly altered IFN polarization, downregulated interferon responsive genes, and induced immunoretrained neutrophils withelevations of the decoy IL-1R2 regulatory receptor. Steroids induced the emergence of immature neutrophils expressing immunosuppressive molecules ARG1 and ANXA1. Moreover, steroids remodeled global cellular communication hierarchies by changing neutrophils from information receivers into information providers. Importantly, male patients had higher proportions of IFN-active neutrophils and a greater degree of steroid induced attenuation of cellular polarization. Indeed, the highest proportion of IFN-active neutrophils was associated with mortality. These results define neutrophil states unique to COVID-19 when contextualized to other life-threatening infections, thereby enhancing the relevance of our findings at the bedside. Furthermore, the clinical benefits of dexamethasone therapy are molecularly defined, and this information highlights essential molecular pathways to which improved therapeutic targeting can now be conceived.<br>

SARS-CoV-2（严重急性呼吸综合征冠状病毒2型）是一种新型冠状病毒，可引发急性呼吸窘迫综合征（ARDS）并导致死亡。先天免疫细胞在宿主防御过程中发挥关键作用，但同时也是急性呼吸窘迫综合征的主要致病驱动因素。相较于细菌性脓毒症等其他病因引发的ARDS，新冠病毒感染所致ARDS中的先天细胞应答关联机制尚不明确。此外，重症新冠患者接受地塞米松治疗所产生的有益细胞效应仍有待进一步验证，但阐明其作用机制或可推动理性化靶向药物研发。本研究发现，与细菌性脓毒症相关ARDS相比，新冠病毒感染可诱导出特征鲜明的中性粒细胞极化状态，分别以干扰素（IFN）或前列腺素（PG）激活为核心特征。干扰素极化依赖转录调控因子PRDM1、STAT1与IRF1，而前列腺素极化则由E2F4介导诱导。细菌性ARDS患者的中性粒细胞可通过STAT5b通路上调PLAC8等抗菌分子，并表达经典转录因子CEBPA与CEBPB。糖皮质激素治疗可快速改变干扰素极化状态，下调干扰素应答基因，并诱导产生免疫训练型中性粒细胞，同时上调诱骗性受体IL-1R2的表达水平。糖皮质激素还可促使表达免疫抑制分子ARG1与ANXA1的未成熟中性粒细胞大量出现。此外，糖皮质激素通过重塑中性粒细胞的功能角色，将其从信息接收者转变为信息提供者，从而重构全局细胞通讯层级。值得注意的是，男性患者体内IFN激活型中性粒细胞的占比更高，且经糖皮质激素诱导的细胞极化减弱程度更为显著。事实上，IFN激活型中性粒细胞的最高占比与患者死亡率密切相关。本研究明确了相较于其他致命性感染，新冠病毒感染特有的中性粒细胞状态，从而提升了本研究结果的临床相关性。此外，本研究从分子层面阐明了地塞米松治疗的临床获益机制，相关发现可为后续优化靶向治疗策略提供关键分子通路依据。