Biology subjects

Kandler, J.

Publications and source records attributed to Kandler, J..

3 recordsLinked to original sources

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↗

bioRxiv2022

Identification of novel antiviral drug candidates using an optimized SARS-CoV-2 phenotypic screening platform

Reliable, easy-to-handle phenotypic screening platforms are needed for the identification of anti-SARS-CoV-2 compounds. Here, we present caspase 3/7 activity as a read-out for monitoring the replication of SARS-CoV-2 isolates from different variants, including a remdesivir-resistant strain, and of other coronaviruses in a broad range of cell culture models, independently of cytopathogenic effect formation. Compared to other cell culture models, the Caco-2 subline Caco-2-F03 displayed superior performance, as it possesses a stable SARS-CoV-2 susceptible phenotype and does not produce false-positive hits due to drug-induced phospholipidosis. A proof-of-concept screen of 1796 kinase inhibitors identified known and novel antiviral drug candidates including inhibitors of PHGDH, CLK-1, and CSF1R. The activity of the PHGDH inhibitor NCT-503 was further increased in combination with the HK2 inhibitor 2-deoxy-D-glucose, which is in clinical development for COVID-19. In conclusion, caspase 3/7 activity detection in SARS-CoV-2-infected Caco-2F03 cells provides a simple phenotypic high-throughput screening platform for SARS-CoV-2 drug candidates that reduces false positive hits.

pharmacology and toxicology↗

bioRxiv2021

CD47 as a potential biomarker for the early diagnosis of severe COVID-19

The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Most SARS-CoV-2 infections are mild or even asymptomatic. However, a small fraction of infected individuals develops severe, life-threatening disease, which is caused by an uncontrolled immune response resulting in hyperinflammation. Antiviral interventions are only effective prior to the onset of hyperinflammation. Hence, biomarkers are needed for the early identification and treatment of high-risk patients. Here, we show in a range of model systems and data from post mortem samples that SARS-CoV-2 infection results in increased levels of CD47, which is known to mediate immune escape in cancer and virus-infected cells. Systematic literature searches also indicated that known risk factors such as older age and diabetes are associated with increased CD47 levels. High CD47 levels contribute to vascular disease, vasoconstriction, and hypertension, conditions which may predispose SARS-CoV-2-infected individuals to COVID-19-related complications such as pulmonary hypertension, lung fibrosis, myocardial injury, stroke, and acute kidney injury. Hence, CD47 is a candidate biomarker for severe COVID-19. Further research will have to show whether CD47 is a reliable diagnostic marker for the early identification of COVID-19 patients requiring antiviral therapy.

microbiology↗