A new single-cell RNA sequencing analysis of more than 59,000 cells from three different patient cohorts provides a detailed look at patients’ immune responses to severe cases of COVID-19. The results suggest that patients with severe COVID-19 experience increased regulation of the type I interferon (IFN-I) inflammation-triggering pathway – a signature that the researchers also observed in patients hospitalized with severe cases of influenza. Their findings suggest that anti-inflammatory treatment strategies for COVID-19 should also be aimed toward the IFN-I signaling pathway, in addition to targeting inflammatory molecules such as TNF, IL-1?, and IL-6 that have been implicated in COVID-19. Seong Seok Lee and colleagues sequenced the RNA from a total of 59,572 blood cells obtained from four healthy donors, eight patients with mild or severe COVID-19, and five patients with severe influenza. Patients in both the mild and severe COVID-19 cohorts all showed increased regulation of the TNF/IL-1ß-driven inflammatory response, while patients with severe COVID-19 also exhibited an increased IFN-I response. By comparison, patients with severe flu showed increased expression of various IFN-stimulated genes, but did not experience TNF/IL-1ß responses as seen in COVID-19 patients. Unlike the flu cohort, patients in the severe COVID-19 cohort exhibited the IFN-I signature concurrently with TNF/IL-1ß-driven inflammation – a combination also not seen in patients with milder cases of COVID-19. Based on their results, the scientists propose that the IFN-I response exacerbates inflammation in patients with severe COVID-19. Their results, along with past mouse studies that highlight how the timing of IFN-I expression is critical to determining the outcome of SARS-CoV-2 infection, support targeting IFN-I as a potential treatment strategy for severe COVID-19.