Adjusting susceptibilities of C57BL/6 mice to orthoflaviviruses for evaluation of antiviral drugs by altering the levels of interferon alpha/beta receptor function

• Published in: Journal of virological methods 2025-01, Vol.331, p.115053, Article 115053
• Main Authors: Morrey, John D., Siddharthan, Venkatraman
• Format: Article
• Language: English
• Subjects: 7-deaza-2’-C-methyladensosine; Animals; Antiviral; Antiviral Agents - pharmacology; Deer tick virus; Disease Models, Animal; Disease Susceptibility; Encephalitis Virus, Japanese - drug effects; Encephalitis Virus, Japanese - immunology; Encephalitis Viruses, Tick-Borne - drug effects; Flavivirus - drug effects; Flavivirus Infections - virology; Flaviviruses; Japanese encephalitis virus; Mice; Mice, Inbred C57BL; Mice, Knockout; Orthoflaviviruses; Receptor, Interferon alpha-beta - genetics; Type 1 interferon; Usutu virus; West Nile virus; West Nile virus - drug effects
• ISSN: 0166-0934; 1879-0984; 1879-0984
• DOI: 10.1016/j.jviromet.2024.115053

The purpose of this study was to optimize the infectivity of four different orthoflaviviruses in mice for evaluating antiviral drugs by using wild-type mice with intact interferon responses, type 1 interferon alpha/beta receptor knockout mice, or by injecting wild type C57BL/6 mice with varying doses of anti-type 1 interferon receptor antibody (MAR1-5A3) to optimize the infectivity and lethality. West Nile virus productively infected wild-type C57BL/6 mice to cause lethality, whereas Usutu virus required a complete absence of type 1 interferon receptor function. Deer tick virus (lineage 2 Powassan virus) and Japanese encephalitis viruses required a dampening of type 1 interferon responses by adjusting the doses of MAR1-5A3 antibody injections. Challenge dose-responsive mortality, weight loss, and viral titers of these two viruses were observed if the type 1 interferon responses were dampened with MAR1-5A3. Conversely, without MAR1-5A3 injections, these disease phenotypes were not viral challenge dose-responsive. From these different interferon-responsive models, the appropriate lethality was identified to determine that 7-deaza-2’-C-methyladenosine has high efficacy for West Nile and Usutu viruses, and low efficacy for deer tick and Japanese encephalitis viruses. •Orthoflavivirus infections were optimized by adjusting anti-IFNAR antibody dose in mice.•Mortality and challenge dose-responsiveness was achieved with anti-IFNAR antibody.•Antiviral activity was readily identified by optimizing dosage of IFNAR antibody.