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

Yuxia Lin, Mona Khan, Birgit Weynand, Manon Laporte, Frank Coenjaerts, Darius Babusis, John P. Bilello, Peter Mombaerts, Dirk Jochmans and Johan Neyts ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52071-5

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