Multiple LDLR family members act as entry receptors for yellow fever virus
Summary
The authors used a focused cell-surface CRISPR–Cas9 screen and follow-up biochemical and in vivo studies to show that multiple members of the low-density lipoprotein receptor (LDLR) family — notably LRP4, LRP1 and VLDLR — can act as entry receptors for yellow fever virus (YFV). LRP4 was identified as a top hit; binding assays and receptor ectodomain Fc-fusion decoys block YFV infection in cultured cells and reduce viral RNA levels in mouse models. The work maps receptor–virus interactions to specific LDLR family ligand-binding domains, examines tissue expression patterns, and tests decoy molecules in several animal models, supporting a model in which different LDLR-family members can mediate YFV attachment and entry and contribute to tropism and pathogenesis.
Key Points
- A CRISPR screen of cell-surface genes identified LRP4 as required for efficient YFV infection; knockout and complementation experiments validated the finding.
- Biophysical assays (binding of virions to receptor ectodomains) show direct interaction between YFV and multiple LDLR-family ligand-binding domains.
- Fc-fusion decoy proteins derived from LRP4, LRP1 and VLDLR can inhibit YFV infection in cell lines and lower viral RNA in infected mice when administered as decoys.
- Tissue expression data for LRP4, LRP1 and VLDLR were analysed, linking receptor distribution to possible viral tropism in humans and mice.
- The study provides structural and functional mapping to specific LA/ligand-binding repeats that mediate virus binding, highlighting potential targets for antiviral decoys or therapeutics.
- Data and code are openly available: supplementary information, sequencing accessions and an SPR analysis script are provided by the authors.
Context and relevance
Yellow fever remains a serious flavivirus threat in parts of Africa and South America and understanding host entry factors is key for both antiviral design and interpretation of tissue tropism and disease severity. This paper extends recent findings that viruses often exploit members of the LDLR family as gateways for cell entry (parallels with alphaviruses and other arboviruses) and positions LRP4, LRP1 and VLDLR as important host factors for YFV. The identification of receptor domains that bind virions and the demonstration that soluble receptor ectodomains can act as decoys make this directly relevant to antiviral strategy development and to fundamental studies of flavivirus–host interactions.
Author style
Punchy: the team nail down a clear new set of YFV entry factors and back the claim with CRISPR genetics, binding assays and in vivo decoy experiments. If you care about flavivirus entry, antiviral decoys or viral tropism, read the details — there are potential translational hooks here.
Why should I read this?
Short version: they found the doors YFV uses to get into cells and showed you can jam those doors with decoy proteins. It’s not just one receptor — several related LDLR family members can be used — which matters if you’re thinking about where the virus goes in the body or how to stop it. If antivirals, vaccines or pathogenesis are on your agenda, this saves you the slog of paging through dense methods: the main takeaway and the potential therapeutic angle are laid out clearly.