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Cytomegalovirus pentamer dependent endocytic cellular infection utilizes redundant entry receptors in the guinea pig

Yushu Qin, K Yeon Choi, Alistair McGregor

    Biorxiv : the Preprint Server for Biology
    |May 18, 2026
    PubMed

    Insights

    The guinea pig cytomegalovirus (GPCMV) model reveals distinct cell entry pathways, with specific receptors like PDGFRA and NRP2 determining infection routes. Understanding these mechanisms is crucial for developing effective congenital CMV (cCMV) interventions.

    Area of Science:

    • Virology
    • Cell Biology
    • Immunology

    Background:

    • Congenital cytomegalovirus (cCMV) is a significant cause of newborn hearing loss and cognitive impairment.
    • The guinea pig model using guinea pig cytomegalovirus (GPCMV) is essential for studying cCMV due to species-specific viral requirements.
    • GPCMV utilizes distinct entry pathways, including direct and endocytic routes mediated by specific viral complexes.

    Purpose of the Study:

    • To elucidate the specific cellular receptors involved in GPCMV entry into different guinea pig cell types.
    • To compare GPCMV infection tropism and receptor usage in fibroblasts versus epithelial cells.
    • To evaluate the potential of targeting viral entry mechanisms for therapeutic strategies against cCMV.

    Main Methods:

    • Utilized knockout cell lines (PDGFRA, NRP2, ThBD) to investigate GPCMV receptor function.
    • Compared GPCMV infection efficiency and tropism between fibroblast and epithelial cell lines.
    • Employed immunoprecipitation assays to study interactions between viral complexes and cellular receptors.
    • Assessed the impact of receptor knockout on GPCMV neutralization by gB antibodies.

    Main Results:

    • PDGFRA mediates direct GPCMV entry in fibroblasts, while NRP2 is crucial for endocytic entry in epithelial cells.
    • Epithelial cells require the pentamer complex (PC) for GPCMV infection and express ThBD, which interacts with PC.
    • Double knockout of NRP2/ThBD in epithelial cells significantly impaired GPCMV infection, highlighting their combined role.
    • GPCMV infection of epithelial cells is dependent on PC, unlike fibroblast entry.
    • Knockout of NRP2/ThBD did not enhance gB antibody neutralization, indicating limitations for gB-based vaccines.

    Conclusions:

    • GPCMV employs distinct receptor-mediated entry pathways (PDGFRA for direct, NRP2/ThBD/PC for endocytic) in different cell types.
    • The identified receptors and tropism patterns in the guinea pig model closely mirror human CMV (HCMV), reinforcing its translational value.
    • Understanding these GPCMV entry mechanisms is critical for developing targeted interventions and vaccines for cCMV.
    • Limitations exist for gB-based vaccine strategies due to the dependence on PC for endocytic entry.

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