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bioRxiv · 10.1101/2025.05.31.657153

Dengue virus suppression by 25-hydroxycholesterol is mediated by a combination of membrane fusion inhibition, innate immune activation and cholesterol biosynthesis dysregulation

Chakraborty, D.·Sannigrahi, A.·Kaif, M.·Patra, A.·Thakkar, D.·Roy, R.
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Abstract

Physicochemical properties and composition of cellular membranes are crucial for regulating broad cellular responses including signaling and defense against pathogens. Dengue virus (DENV) exploits cholesterol-rich membranes and host lipid pathways, such as cholesterol biosynthesis, lipid raft organization, and lipid droplet formation, for entry, replication, and assembly. Additionally, lipid-based plasma membrane signaling can trigger innate immune responses that attenuate viral growth, underscoring the dual role of lipids in facilitating and restricting DENV infection. Here, we demonstrate that 25-hydroxycholesterol (25-HC), an oxidized cholesterol metabolite, inhibits DENV infection through a multifaceted mechanism. 25-HC disrupts viral membrane fusion by altering cholesterol distribution and lipid raft organization, impairing the binding and fusion of the DENV envelope (E) protein with host membranes. Additionally, 25-HC modulates host cholesterol metabolism by suppressing biosynthesis pathways essential for viral replication while enhancing lipid droplet formation and stress-response pathways. Transcriptomic analyses reveal that 25-HC primes innate immune responses, activating proinflammatory pathways such as the NLRP3 inflammasome and MAPK signaling, while selectively modulating interferon-stimulated gene expression. Notably, 25-HC exhibits synergistic antiviral effects when combined with direct-acting antivirals like Remdesivir, underscoring its potential in combination therapies. These findings establish 25-HC as a promising candidate for host-directed antiviral strategies against DENV and other enveloped viruses.

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Chakraborty, D., Sannigrahi, A., Kaif, M., Patra, A., Thakkar, D., Roy, R.. 2025-06-03. Dengue virus suppression by 25-hydroxycholesterol is mediated by a combination of membrane fusion inhibition, innate immune activation and cholesterol biosynthesis dysregulation. https://doi.org/10.1101/2025.05.31.657153

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