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A robust mouse model of HPIV-3 infection and efficacy of GS-441524 against virus-induced lung pathology

Author

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  • Yuxia Lin

    (Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group)

  • Mona Khan

    (Max Planck Research Unit for Neurogenetics)

  • Birgit Weynand

    (Division of Translational Cell and Tissue Research)

  • Manon Laporte

    (Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group)

  • Frank Coenjaerts

    (University Medical Center Utrecht, Utrecht University)

  • Darius Babusis

    (Gilead Sciences Incorporated)

  • John P. Bilello

    (Gilead Sciences Incorporated)

  • Peter Mombaerts

    (Max Planck Research Unit for Neurogenetics)

  • Dirk Jochmans

    (Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group)

  • Johan Neyts

    (Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group
    KU Leuven)

Abstract

Human parainfluenza virus type 3 (HPIV-3) can cause severe respiratory tract infections. There are no convenient small-animal infection models. Here, we show viral replication in the upper and lower airways of AG129 mice (double IFNα/β and IFNγ receptor knockout mice) upon intranasal inoculation. By multiplex fluorescence RNAscope and immunohistochemistry followed by confocal microscopy, we demonstrate viral tropism to ciliated cells and club cells of the bronchiolar epithelium. HPIV-3 causes a marked lung pathology. No virus transmission of the virus was observed by cohousing HPIV-3-infected AG129 mice with other mice. Oral treatment with GS-441524, the parent nucleoside of remdesivir, reduced infectious virus titers in the lung, with a relatively normal histology. Intranasal treatment also affords an antiviral effect. Thus, AG129 mice serve as a robust preclinical model for developing therapeutic and prophylactic strategies against HPIV-3. We suggest further investigation of GS-441524 and its prodrug forms to treat HPIV-3 infection in humans.

Suggested Citation

  • Yuxia Lin & Mona Khan & Birgit Weynand & Manon Laporte & Frank Coenjaerts & Darius Babusis & John P. Bilello & Peter Mombaerts & Dirk Jochmans & Johan Neyts, 2024. "A robust mouse model of HPIV-3 infection and efficacy of GS-441524 against virus-induced lung pathology," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52071-5
    DOI: 10.1038/s41467-024-52071-5
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    References listed on IDEAS

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    1. Robert M. Cox & Josef D. Wolf & Carolin M. Lieber & Julien Sourimant & Michelle J. Lin & Darius Babusis & Venice DuPont & Julie Chan & Kim T. Barrett & Diane Lye & Rao Kalla & Kwon Chun & Richard L. M, 2021. "Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
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