A robust mouse model of HPIV-3 infection and efficacy of GS-441524 against virus-induced lung pathology
Yuxia Lin1, Mona Khan2, Birgit Weynand3
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group, Leuven, Belgium.
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.
Insights
A new mouse model using AG129 mice allows studying human parainfluenza virus type 3 (HPIV-3) respiratory infections. Treatment with GS-441524 showed antiviral effects, suggesting potential therapies for HPIV-3.
Area of Science:
- Virology
- Immunology
- Respiratory Medicine
Background:
- Human parainfluenza virus type 3 (HPIV-3) causes severe respiratory infections.
- Lack of suitable small-animal models hinders HPIV-3 research and therapeutic development.
Purpose of the Study:
- To establish and validate a small-animal model for HPIV-3 infection.
- To investigate the efficacy of GS-441524 as a potential antiviral treatment for HPIV-3.
Main Methods:
- Intranasal inoculation of AG129 mice (IFNα/β and IFNγ receptor knockout) with HPIV-3.
- Viral tropism determined by RNAscope and immunohistochemistry.
- Pathology assessed via histology.
- Antiviral efficacy of GS-441524 evaluated through oral and intranasal administration.
Main Results:
- AG129 mice exhibited viral replication in upper and lower airways, targeting ciliated and club cells.
- HPIV-3 infection induced significant lung pathology.
- No HPIV-3 transmission observed between cohoused mice.
- GS-441524 treatment reduced viral titers and lung pathology.
Conclusions:
- AG129 mice provide a robust preclinical model for HPIV-3.
- GS-441524 demonstrates therapeutic potential against HPIV-3 infection.
- Further research into GS-441524 and its prodrugs for human HPIV-3 treatment is warranted.
