Zaragkoulias, A. | bioRxiv Science

bioRxiv2025

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

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-6R) 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. Significance statementViruses such as SARS-CoV-2 are surrounded by a host-derived lipid envelope. Little is known about how this changes during infection/inflammation. We determined the lipid composition of the SARS-CoV-2 envelope using both laboratory-grown viruses and patient isolates. Across several pandemic strains, the envelope was rich in cholesterol and phospholipids and showed a consistent structure. Lipids linked to thrombosis and infection were mainly exposed on the outer virus surface. The inflammatory cytokine interleukin-4 altered the envelopes fatty acid composition, while other treatments did not. Patient-derived viruses contained additional bioactive lipids, and blocking an enzyme that generates these lipids reduced coronavirus replication. In summary, the envelope is an active component of infection and potential target for new treatments to dampen infectivity and thrombosis.

immunology↗

bioRxiv2020

KRASG12D mutant cells are outcompeted by wild type neighbours in adult pancreas in an EPHA2-dependent manner.

As we age, our tissues are repeatedly challenged by mutational insult, yet cancer occurrence is a relatively rare event. Cells carrying cancer-causing genetic mutations compete with normal neighbours for space and survival in tissues. However, the mechanisms underlying mutant-normal competition in adult tissues and the relevance of this process to cancer remain incompletely understood. Here, we investigate how the adult pancreas maintains tissue health in vivo following sporadic expression of oncogenic Kras (KrasG12D), the key driver mutation in human pancreatic cancer. We find that when present in tissues in low numbers, KrasG12D mutant cells are outcompeted and cleared from exocrine and endocrine compartments in vivo. Using quantitative 3D tissue imaging, we show that prior to being cleared, KrasG12D cells lose cell volume, segregate from normal cells and decrease E-cadherin-based cell-cell adhesions with normal neighbours. We identify EphA2 receptor is an essential signal in the clearance of KrasG12D cells from exocrine and endocrine tissues in vivo. In the absence of functional EphA2, KrasG12D cells no longer segregate, E-cadherin-based cell-cell adhesions increase and KrasG12D cells are retained in tissues. Retention of KRasG12D cells leads to an increased burden of premalignant pancreatic intraepithelial neoplasia (PanINs) in tissues. Our data show that adult pancreas tissues remodel to clear KrasG12D cells and maintain tissue health. This study provides evidence to support a conserved functional role of EphA2 in Ras-driven cell competition in epithelial tissues and suggests that EphA2 is a novel tumour suppressor in pancreatic cancer.

cell biology↗