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>