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Multiple LDLR family members act as entry receptors for yellow fever virus
Zhenlu Chong1, Sean Hui2, Xueer Qiu3
1Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Abstract:
Infection by yellow fever virus (YFV), the prototype Orthoflavivirus, induces a febrile syndrome in humans that can progress to liver failure, haemorrhage and death1. Despite decades of study, the entry receptors for YFV remain unclear. Here, using a surface protein-targeted CRISPR-Cas9 screen, we identified LRP4, a low-density lipoprotein receptor (LDLR) family member, as a candidate entry receptor for YFV. Genetic ablation of LRP4 impaired YFV infection of cells and, reciprocally, complementation or ectopic expression of LRP4 increased infection. Related viruses in the YFV antigenic complex also showed LRP4-dependent infection. LRP4 promoted YFV entry into cells through LDLR type A (LA) domain binding to domain III of the YFV envelope protein. Soluble LRP4-Fc decoy receptors neutralized YFV infection in cell culture and reduced viral burden in vivo. As we observed residual YFV infection in LRP4-deficient cells, we evaluated whether other LDLR family members promote YFV entry. This approach identified LRP1 and VLDLR as additional receptors for YFV infection in cell culture. LRP1-Fc, LRP4-Fc and VLDLR-Fc decoys protected mice from YFV challenge, and LRP1-Fc decoys inhibited YFV infection and liver pathogenesis in mice engrafted with human hepatocytes. A genetic deficiency of LRP1 in primary human hepatocyte cultures also resulted in reduced YFV infection. Our findings establish a role for multiple LDLR family members in YFV entry, infection and pathogenesis, which has implications for receptor use and countermeasure development for multiple emerging orthoflaviviruses.
Insights
Researchers identified LRP4 as a key entry receptor for yellow fever virus (YFV). This discovery, along with LRP1 and VLDLR, offers new avenues for developing countermeasures against YFV and related flaviviruses.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Yellow fever virus (YFV) is a significant human pathogen.
- The cellular entry mechanisms of YFV are not fully understood.
- Identifying YFV entry receptors is crucial for developing antiviral strategies.
Purpose of the Study:
- To identify the cellular entry receptors for yellow fever virus (YFV).
- To investigate the role of low-density lipoprotein receptor (LDLR) family members in YFV infection.
- To explore potential therapeutic targets for YFV and related orthoflaviviruses.
Main Methods:
- CRISPR-Cas9 screening to identify surface protein receptors.
- Genetic manipulation (ablation, complementation, ectopic expression) of candidate receptors.
- In vitro cell culture infection assays.
- In vivo studies using mouse models and humanized mouse models.
- Development and testing of soluble decoy receptors (Fc-fusion proteins).
Main Results:
- Low-density lipoprotein receptor 4 (LRP4) was identified as a YFV entry receptor.
- LRP4 mediates YFV entry via binding to the YFV envelope protein.
- Related viruses within the YFV antigenic complex also utilize LRP4.
- LRP1 and Very low-density lipoprotein receptor (VLDLR) were identified as additional YFV entry receptors.
- Soluble decoy receptors (LRP1-Fc, LRP4-Fc, VLDLR-Fc) demonstrated protective effects in vitro and in vivo.
- LRP1 deficiency in human hepatocytes reduced YFV infection.
Conclusions:
- Multiple LDLR family members, including LRP4, LRP1, and VLDLR, serve as entry receptors for YFV.
- These receptors play a significant role in YFV infection and pathogenesis.
- The identified receptors and decoy strategies have implications for developing countermeasures against YFV and other emerging orthoflaviviruses.
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