Yellow Fever Virus Enters New Territory: LRP8 Identified as a Key Human Receptor
Yellow fever virus (YFV) has remained one of the most formidable arboviruses, responsible for significant outbreaks causing morbidity and mortality worldwide, particularly in tropical regions. Despite successful control measures such as the widely used live-attenuated 17D vaccine, much about the virus’s interaction with host cells continues to puzzle researchers. A new breakthrough study now uncovers a critical human receptor, LRP8 (also known as APOER2), which fundamentally alters our understanding of how YFV gains entry into cells and spreads in the human body.
At the heart of this research is a sophisticated, barcoded genome-wide human open-reading frame (ORF) screen deployed to systematically hunt for host factors that facilitate YFV infection. This powerful genetic approach enabled researchers to scan the entire human proteome for candidates that increase susceptibility to YFV, unearthing LRP8 as a standout receptor. Prior to this, receptor usage distinctions between attenuated vaccine strains and pathogenic variants were poorly understood, leaving a major gap in the knowledge of YFV cell entry and tropism.
The study’s experiments revealed that expression of LRP8 significantly enhances infection by the 17D vaccine strain as well as by two pathogenic clinical isolates — BJ01 and Asibi — across various human cell lines. The mechanism identified revolves around LRP8 acting as a gateway that promotes viral entry. This means LRP8 on the cell surface directly interacts with the YFV particles, effectively tethering the virus and facilitating its subsequent internalization into the host cell.
To push beyond cell culture, the researchers utilized adeno-associated virus vectors to express human LRP8 in mouse liver cells. This in vivo model demonstrated that LRP8 expression worsened both the infection outcome and liver pathology caused by the BJ01 clinical strain. Such findings underscore LRP8’s role not just in virus entry, but in driving disease progression, amplifying viral replication and tissue damage within a live organism.
Further emphasizing the importance of LRP8, knockdown studies in multiple systems helped clarify its essential role. Reducing LRP8 expression significantly decreased YFV infection rates not only in brain-derived cell lines and primary human hepatocytes but also in mosquitoes, the natural vectors that propagate arboviruses. This suggests that LRP8 is functionally relevant across diverse biological contexts, making it a universal facilitator of YFV transmission and pathogenesis.
Biochemical and biophysical assays confirmed the direct interaction between LRP8 and the viral envelope protein of YFV 17D particles. This envelope glycoprotein mediates crucial steps in virus entry, and the identification of LRP8 as its binding partner elucidates a vital molecular engagement previously unknown. The recognition of this receptor-ligand pair helps explain tissue-specific targeting by the virus as well as species-specific barriers in host infectivity.
Intriguingly, the researchers developed a soluble decoy protein derived from the extracellular domain of LRP8 that competitively inhibited YFV infection by blocking the interaction between virus and cellular receptor. This decoy protein efficiently prevented infection by both vaccine and clinical YFV strains in vitro, highlighting a promising therapeutic avenue to intercept viral entry before the onset of replication and disease.
This discovery holds implications beyond yellow fever virus biology. LRP8, widely expressed in the central nervous system and liver—tissues heavily impacted by YFV—adds a mechanistic explanation for viral tropism and the resultant neurological and hepatic damage seen in severe cases. Understanding the molecular determinants of viral attachment and entry opens doors for the rational design of antiviral agents tailored to exploit these vulnerabilities.
The uncovering of LRP8’s role also extends to vector biology. Since knockdown in mosquitoes reduced viral infection within these insects, this receptor may participate in viral maintenance in vector populations, representing a target for vector-based interventions aimed at breaking the cycle of transmission in endemic regions.
By bridging the gap between virus and host, identifying LRP8 redefines the landscape of yellow fever virus research. It challenges prior assumptions about receptor restriction and presents a unified model linking vaccine and wild-type strains through a shared entry pathway, bringing coherence to previously disparate observations about YFV infection.
This research not only illuminates YFV pathogenesis but also propels the frontier of flavivirus biology. The methodological framework combining genome-wide screening with in vivo models and biochemical validation establishes a blueprint for deciphering viral receptors for other arboviruses, a class including dengue, Zika, and West Nile viruses, whose entry mechanisms remain enigmatic.
Moreover, the therapeutic potential offered by soluble receptor decoys signifies a strategic breakthrough. Such molecules can serve as decoy receptors or viral traps, impeding virus access to true cellular receptors and offering an alternative or adjunct to traditional vaccine-based prevention, which may face challenges due to viral evolution or vaccine hesitancy.
The findings also underline how viral receptor usage can shape host range and tissue targeting, critical for understanding zoonosis spillover and viral emergence. With LRP8 expression pattern influencing susceptibility in key organs like liver and brain, these results provide insight into why yellow fever exhibits its characteristic clinical manifestations and how viral dissemination occurs within the host.
To translate these insights into public health impact, further studies addressing the structure-function relationship between LRP8 and the YFV envelope protein will be essential. Detailed atomic-level interactions could inform the design of small-molecule inhibitors or monoclonal antibodies that disrupt entry. Additionally, understanding the regulation of LRP8 expression in human populations could identify at-risk groups or explain differential disease outcomes.
In summary, this groundbreaking work identifies LRP8/APOER2 as a crucial human receptor for yellow fever virus, fundamentally advancing knowledge on viral entry, tropism, and pathogenesis. Through comprehensive approaches spanning molecular biology, animal models, and vector studies, the research offers promising paths for novel antiviral interventions and deepens the understanding of flavivirus-host interplay, a cornerstone in the ongoing battle against yellow fever.
Subject of Research: Identification and characterization of LRP8 as a functional receptor mediating yellow fever virus entry and infection.
Article Title: LRP8 is a functional receptor for yellow fever virus.
Article References: Mei, M., Yang, Y., Zhang, Z. et al. LRP8 is a functional receptor for yellow fever virus. Nat Microbiol (2026). https://doi.org/10.1038/s41564-026-02278-7
Image Credits: AI Generated
