Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Mucosal Immunol. 2023 Dec;16(6):843-858. doi: 10.1016/j.mucimm.2023.09.004. Epub 2023 Sep 18.
Influenza virus-induced respiratory pneumonia remains a major public health concern. Obesity, metabolic diseases, and female sex are viewed as independent risk factors for worsened influenza virus-induced lung disease severity. However, lack of experimental models of severe obesity in female mice limits discovery-based studies. Here, via utility of thermoneutral housing (30 °C) and high-fat diet (HFD) feeding, we induced severe obesity and metabolic disease in female C57BL/6 mice and compared their responses to severely obese male C57BL/6 counterparts during influenza virus infection. We show that lean male and female mice have similar lung edema, inflammation, and immune cell infiltration during influenza virus infection. At standard housing conditions, HFD-fed male, but not female, mice exhibit severe obesity, metabolic disease, and exacerbated influenza disease severity. However, combining thermoneutral housing and HFD feeding in female mice induces severe obesity and metabolic disease, which is sufficient to amplify influenza virus-driven disease severity to a level comparable to severely obese male counterparts. Lastly, increased total body weights of male and female mice at time of infection correlated with worsened influenza virus-driven disease severity metrics. Together, our findings confirm the impact of obesity and metabolic disease as key risk factors to influenza disease severity and present a novel mouse experimental model suitable for future mechanistic interrogation of sex, obesity, and metabolic disease traits in influenza virus-driven disease severity.
流感病毒引起的呼吸道肺炎仍然是一个主要的公共卫生关注点。肥胖、代谢疾病和女性性别被认为是流感病毒引起的肺部疾病严重程度恶化的独立危险因素。然而，缺乏肥胖雌性小鼠的严重肥胖实验模型限制了基于发现的研究。在这里，我们通过使用常温饲养（30°C）和高脂肪饮食（HFD）饲养，在雌性 C57BL/6 小鼠中诱导严重肥胖和代谢疾病，并比较它们在流感病毒感染期间对严重肥胖雄性 C57BL/6 对应物的反应。我们表明，在流感病毒感染期间，瘦的雄性和雌性小鼠的肺部水肿、炎症和免疫细胞浸润相似。在标准饲养条件下，HFD 喂养的雄性但不是雌性小鼠表现出严重肥胖、代谢疾病和流感疾病严重程度恶化。然而，在雌性小鼠中结合常温饲养和 HFD 饲养会诱导严重肥胖和代谢疾病，足以将流感病毒驱动的疾病严重程度放大到与严重肥胖雄性对应物相当的水平。最后，感染时雄性和雌性小鼠的总体重增加与流感病毒驱动的疾病严重程度指标恶化相关。总之，我们的发现证实了肥胖和代谢疾病是流感疾病严重程度的关键危险因素，并提出了一种新的小鼠实验模型，适合未来对流感病毒驱动的疾病严重程度中的性别、肥胖和代谢疾病特征进行机制研究。
