A robust mouse model of human parainfluenza 3 virus infection and efficacy of GS-441524, the parent nucleoside of remdesivir, against lung pathology

Human parainfluenza virus type 3 (HPIV-3) can cause severe respiratory tract infections. The development of vaccines and antivirals is hampered by the lack of convenient small-animal infection models. Here, we show that intranasal inoculation of AG129 mice (double IFNα/β and IFNγ receptor knockout mice) with HPIV-3 leads to viral replication in the upper and lower airways, with peak viral loads on days 1-3 post-infection. By multiplex fluorescence RNAscope and immunohistochemistry followed by confocal microscopy, we demonstrate viral tropism to ciliated cells and club cells of the bronchiolar epithelium. From day 5 post-infection, a marked lung pathology develops, with perivascular and peribronchial inflammation, bronchopneumonia, and hyperplasia of pneumocytes. Oral treatment with GS-441524, the parent nucleoside of remdesivir, drastically reduces infectious virus titers in the lung, with a relatively normal histology. Intranasal treatment also affords an antiviral effect. We conclude that AG129 mice serve as a robust preclinical model for developing therapeutic and prophylactic strategies against HPIV-3. Our results support further evaluation of GS-441524 and its prodrug forms as potential treatment of HPIV-3 infection in humans.