The coronavirus envelope is conserved, contains bioactive lipids needed for replication, and is modulated in response to host inflammation

Like all coronaviruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is surrounded by a lipid envelope hosting spike and other critical proteins. However, little is known about the biology of coronavirus membranes, their regulation by inflammation/disease, nor how they could be harnessed to dampen infection. Here, we show using lipidomics that four cultured SARS-CoV-2 strains (England2 (Wuhan), Alpha (B.1.1.7), Beta (B.1.351) and Delta (B.1.617.2)) contain highly conserved phospholipid (PL)/cholesterol-rich membranes. PL that drive blood clotting and support infectivity (phosphatidylserine (PS) and phosphatidylethanolamine (PE)) were 70-80% external-facing, particularly for Alpha and Beta strains. Interleukin-4 (IL-4) caused a 10-fold increase in secreted virions with dramatically-altered phospholipid fatty acyl saturation. In contrast, envelopes were not impacted by IL-6 (with/without its soluble receptor IL-6Ra) or dexamethasone-treatment of host cells. SARS-CoV-2 membranes isolated from patients were remarkably conserved and cholesterol enriched. Several pro-coagulant oxidized phospholipid damage-associated molecular patterns (DAMPs) and oxylipins generated by lipoxygenases (LOX), were detected in clinical viruses. Furthermore, using gene silencing, we found that 15-LOX2 was required for replication of coronaviruses MERS-CoV and HCoV-229E in macrophages, indicating a shared requirement for LOX products. In summary, the coronavirus envelope contains numerous bioactive lipids with known impacts on inflammation and thrombosis, as well supporting replication, and is altered by disease-relevant host inflammatory factors. This confirms the envelope as a target for therapeutic strategies via direct modulation of host innate immunity.