The coronavirus envelope is modulated by host inflammation and enriched in bioactive lipids required for replication

Tyrrell, Victoria J., Zaragkoulias, Andreas, Powell, Wendy ORCID: https://orcid.org/0000-0002-4670-1406, Elfar, Miran Y., Grossoni, Valeria, Monaco, Federica, Protty, Majd B., Stenhouse, Ewan H. ORCID: https://orcid.org/0000-0002-2524-1914, Heyman, James, Costa, Daniela ORCID: https://orcid.org/0000-0001-8821-5898, Roche, Lisa, Lynch, Ceri-Ann Brigid, Ghazal, Peter, Jones, Simon A. ORCID: https://orcid.org/0000-0001-7297-9711, Lambeau, Gérard, Benatzy, Yvonne, Kandler, Joshua D., Bojkova, Denisa, Snodgrass, Ryan G., Brüne, Bernhard, Thomas, David W., Stanton, Richard J. ORCID: https://orcid.org/0000-0002-6799-1182 and O’Donnell, Valerie B. ORCID: https://orcid.org/0000-0003-4089-8460 2026. The coronavirus envelope is modulated by host inflammation and enriched in bioactive lipids required for replication. [Online]. bioRxiv: openRxiv. Available at: https://doi.org/10.1101/2025.11.03.686211

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Abstract

How inflammation or disease regulates coronavirus lipid membranes is currently unknown, while patient-derived viral envelopes have never been structurally characterized. Here, we show that four cultured SARS-CoV-2 strains (England2, Alpha, Beta, and Delta) possess conserved, phospholipid- and cholesterol-rich envelopes, with pro-thrombotic and infection-promoting aminophospholipids (aPL) displayed predominantly on the outer leaflet (approximately 70–80%). Exposure to interleukin-4 (IL-4) markedly altered envelope fatty acyl composition, whereas interleukin-6 (with or without its soluble receptor IL-6Rα) and dexamethasone had no detectable effect. Viral envelopes were susceptible to hydrolysis by secretory phospholipase A2 (sPLA2), an enzyme associated with adverse clinical outcomes. SARS-CoV-2 isolated directly from patient saliva exhibited cholesterol-enriched envelopes that were highly conserved across clinical isolates. In addition, clinical samples contained pro-coagulant oxidized phospholipids and bioactive lipoxygenase (LOX)-derived oxylipins. The dominance of external facing pro-coagulant aPL and eoxPL may support known thrombotic complications of severe COVID19 viremia. Last, gene-silencing experiments demonstrated that 15-LOX2 is required for replication of related coronaviruses. Together, these findings reposition the coronavirus envelope as an active, dynamic structure rather than a passive scaffold, and challenge the protein-centric view of viral function. The lipid envelope is proposed as a potential therapeutic target through modulation of host innate immunity, and dampening thrombotic potential.

Item Type:	Website Content
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Schools > Biosciences Research Institutes & Centres > Centre for Trials Research (CNTRR)
Publisher:	openRxiv
Last Modified:	16 Jan 2026 12:30
URI:	https://orca.cardiff.ac.uk/id/eprint/183958

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