Kenney Devin, Matsuo Mao, Unali Giulia, Wacquiez Alan, Saeed Mohsan, Douam Florian
Department of Virology, Immunology and Microbiology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA.
National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02118, USA.
Viruses. 2025 Sep 7;17(9):1225. doi: 10.3390/v17091225.
Preclinical studies in virological research are pivotal to comprehend mechanisms of viral virulence and pathogenesis and evaluate antiviral therapies or vaccines. Mouse models, through access to various genetic strains and amenable reagents, along with their ease of implementation and cost-effectiveness, remain the gold standard for establishing go/no-go thresholds before advancing to non-human primate or clinical studies. In preclinical mouse studies, standardized weight loss thresholds (WLTs)-which correspond to an established percentage of weight change at which animals are humanely euthanized-are a routine metric to quantitatively evaluate the lethality of a viral pathogen and the effectiveness of antiviral countermeasures in preventing fatal viral disease. While it is recognized that WLTs can significantly impact the assessment of viral virulence, they are often established to meet existing ethical or methodological requirements, rather than being based on a specific scientific rationale. Here, we examine how various experimental variables-including mouse and viral strains and the sex ratio within a mouse cohort-influence the ability of a WLT to support the generation of robust mouse models of fatal viral infection. Using various mouse strains and viral pathogens, we report that variations in experimental conditions in mouse preclinical studies can significantly compromise the performance of a non-adjusted WLT to yield an accurate estimate of viral virulence. Our findings advocate for a robust adjustment of WLT to each experimental framework and associated variables to establish mouse models of fatal viral infection that can generate high-resolution data acquisition while upholding ethical standards. Overall, our study provides methodological insights to enhance the unbiased acquisition and benchmarking of viral virulence and antiviral efficacy data in mouse models.
病毒学研究中的临床前研究对于理解病毒毒力和发病机制以及评估抗病毒疗法或疫苗至关重要。小鼠模型由于能够使用各种遗传品系和适用的试剂，且易于实施且具有成本效益，仍然是在推进到非人类灵长类动物或临床研究之前确定通过/不通过阈值的金标准。在临床前小鼠研究中，标准化体重减轻阈值（WLTs）——对应于动物被人道安乐死时既定的体重变化百分比——是定量评估病毒病原体致死率和抗病毒对策预防致命病毒疾病有效性的常规指标。虽然人们认识到WLTs会显著影响病毒毒力的评估，但它们通常是为了满足现有的伦理或方法学要求而设定的，而非基于特定的科学原理。在此，我们研究各种实验变量——包括小鼠和病毒品系以及小鼠群体中的性别比例——如何影响WLT支持生成致命病毒感染稳健小鼠模型的能力。使用各种小鼠品系和病毒病原体，我们报告临床前小鼠研究中实验条件的变化会显著损害未调整的WLT的性能，从而无法准确估计病毒毒力。我们的研究结果主张针对每个实验框架和相关变量对WLT进行有力调整，以建立能够在坚持伦理标准的同时进行高分辨率数据采集的致命病毒感染小鼠模型。总体而言，我们的研究提供了方法学见解，以加强小鼠模型中病毒毒力和抗病毒疗效数据的无偏获取和基准测试。
