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

• Published in: Nature communications 2024-09, Vol.15 (1), p.7765-12, Article 7765
• Main Authors: Lin, Yuxia, Khan, Mona, Weynand, Birgit, Laporte, Manon, Coenjaerts, Frank, Babusis, Darius, Bilello, John P., Mombaerts, Peter, Jochmans, Dirk, Neyts, Johan
• Format: Article
• Language: English
• Subjects: 13/51; 14/19; 14/32; 631/1647/334/1874/345; 64/60; 692/699/1785; 692/699/255/2514; Adenosine - analogs & derivatives; Adenosine - pharmacology; Animal models; Animals; Antiviral Agents - pharmacology; Benzamides; Confocal microscopy; Disease Models, Animal; Epithelium; Female; Histology; Humanities and Social Sciences; Humans; Immunohistochemistry; Infections; Inoculation; Lung - drug effects; Lung - pathology; Lung - virology; Lungs; Mice; Mice, Knockout; multidisciplinary; Parainfluenza; Parainfluenza Virus 3, Human - drug effects; Parainfluenza Virus 3, Human - physiology; Pathology; Phthalimides; Receptor, Interferon alpha-beta - deficiency; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - metabolism; Replication; Respiratory diseases; Respiratory tract; Respiratory tract infection; Respirovirus Infections - drug therapy; Respirovirus Infections - virology; Robustness; Science; Science (multidisciplinary); Tropism; Viral Tropism; Virus Replication - drug effects; Viruses; α-Interferon; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52071-5

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. Human parainfluenza viruses are important respiratory pathogens. Here, the authors develop a robust mouse infection model that upon HPIV-3 infection exhibits viral replication, viral tropism to ciliated cells and club cells and marked lung pathology. Treatment with GS-441524 reduces virus-induced pathology.