LRP8 is a functional receptor for yellow fever virus.

Yellow fever virus (YFV) is an arbovirus causing substantial human morbidity and mortality. The live-attenuated 17D strain serves as vaccine and is one of the most successful vaccines so far. Receptor usage between attenuated and pathogenic YFV strains remains unclear. Here we performed a barcoded, genome-wide human open-reading frame library screen and identified LRP8 (also named APOER2) as a receptor for YFV. We show that LRP8 expression increases YFV infection (17D and two clinical strains, BJ01 and Asibi) in cell lines by promoting entry. Adeno-associated virus-mediated expression of human LRP8 in mouse liver aggravates infection and pathology of the clinical strain BJ01. LRP8 knockdown decreases YFV infection in brain cells, primary human hepatocytes and mosquitoes. LRP8 directly interacts with YFV 17D particles via the viral envelope protein. A soluble LRP8 decoy protein can block YFV 17D and BJ01 infection. Our findings provide insights for understanding YFV entry, tropism and pathogenesis.