COVID-19 comorbidity studies in Syrian hamster models

项目总结 大流行的SARS-CoV-2(严重急性呼吸综合征冠状病毒2)病毒可导致严重和 甚至一些患者的致命感染，主要是那些合并高血压、糖尿病、 肥胖和心血管疾病。此外，免疫功能低下的患者也面临严重的 新冠肺炎，这种疾病是由SARS-CoV-2引起的。动物模型对于检测预防性和非传染性疾病至关重要。 新冠肺炎的治疗方法，但模型概括了与以下疾病相关的主要并存 缺少新冠肺炎。最近，我们为新冠肺炎建立了叙利亚仓鼠的健壮动物模型 研究。在此模型的基础上，我们计划开发和评估糖尿病(目标1)、肥胖 (AIM 2)、心肌病(AIM 3)和免疫低下(AIM 4)叙利亚仓鼠用于新冠肺炎研究。 对于目标1(为新冠肺炎研究评估糖尿病叙利亚仓鼠)，我们已经展示了我们的 通过链脲佐菌素治疗产生糖尿病叙利亚仓鼠的能力，链脲佐菌素是一种常用于 建立糖尿病动物模型。高脂肪饮食将被用来产生肥胖的仓鼠，用于AIM 2的研究 (“为新冠肺炎研究建立肥胖叙利亚仓鼠”)。目标3中的研究(‘评估心肌病 新冠肺炎研究的叙利亚仓鼠)将与BIO14.6叙利亚仓鼠进行，这是一个既定的 心肌病模型。免疫功能低下的状态是通过用 环磷酰胺(一种通常用于诱导免疫抑制的药物)，用于目标4中的研究(‘建立 免疫受损的叙利亚仓鼠用于新冠肺炎研究‘)。特定的标记物，如血糖水平 (糖尿病)、瘦素水平(肥胖)、肌钙蛋白T水平(心血管损伤)和白细胞计数( 免疫抑制)将使我们能够监测疾病状态。动物将被感染SARS冠状病毒- 感染后不同时间点检测不同器官的病毒滴度。此外，我们还将 衡量病毒脱落的持续时间和病毒传播的效率，这两者都可能会增加 与健康的SARS-CoV-2感染的动物相比，是共病的。我们还将评估其易感性 健康和共同患病的叙利亚仓鼠再次感染SARS-CoV-2。在这里测试的合并症 导致慢性炎症和/或免疫反应受损。因此，几个亲-的水平- 这些仓鼠的血清样本中的炎性细胞因子和SARS-CoV-2抗体将被评估。 总而言之，我们将为SARS-CoV-2研究建立和测试几个叙利亚仓鼠共病模型。 我们的数据应该为在疫苗测试中使用共病叙利亚仓鼠模型提供坚实的平台 以及针对SARS-CoV-2的抗病毒化合物。

PROJECT SUMMARY The pandemic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus can cause severe and even fatal infections in some patients, primarily those with comorbidities such as hypertension, diabetes mellitus, obesity, and cardiovascular disease. In addition, immunocompromised patients are also at a high risk of severe COVID-19, the disease caused by SARS-CoV-2. Animal models are vital for the testing of preventative and therapeutic approaches to COVID-19, but models that recapitulate the major comorbidities associated with COVID-19 are lacking. Recently, we established Syrian hamsters as a robust animal model for COVID-19 research. Building on our work with this model, we here plan to develop and evaluate diabetic (Aim 1), obese (Aim 2), cardiomyopathic (Aim 3), and immunocompromised (Aim 4) Syrian hamsters for COVID-19 research. For Aim 1 (‘To evaluate diabetic Syrian hamsters for COVID-19 research’), we have already demonstrated our ability to generate diabetic Syrian hamsters by treating them with streptozotocin, a drug commonly used to establish diabetic animal models. A high-fat diet will be used to generate obese hamsters for studies in Aim 2 (‘To establish obese Syrian hamsters for COVID-19 research’). Studies in Aim 3 (‘To evaluate cardiomyopathic Syrian hamsters for COVID-19 research’) will be conducted with BIO14.6 Syrian hamsters, an established cardiomyopathic disease model. An immunocompromised status will be induced by treating animals with cyclophosphamide (a drug commonly used to induce immunosuppression) for studies in Aim 4 (‘To establish immunocompromised Syrian hamsters for COVID-19 research’). Specific markers, such as blood glucose levels (for diabetes), leptin levels (for obesity), troponin T levels (cardiovascular injury) and leukocytes counts (for immunosuppression) will allow us to monitor the disease states. Animals will then be infected with SARS-CoV- 2, and virus titers in different organs will be measured at different timepoints post-infection. In addition, we will measure the duration of virus shedding and the efficiency of virus transmission, both of which may be increased in co-morbid compared with healthy SARS-CoV-2-infected animals. We will also assess the susceptibility for reinfection with SARS-CoV-2 of both healthy and co-morbid Syrian hamsters. The comorbidities tested here result in chronic inflammation and/or impaired immune responses. Therefore, the levels of several pro- inflammatory cytokines and antibodies to SARS-CoV-2 in serum samples from these hamsters will be evaluated. Collectively, we will establish and test several Syrian hamster comorbidity models for SARS-CoV-2 research. Our data should provide a solid platform for the use of co-morbid Syrian hamster models in the testing of vaccines and antiviral compounds for SARS-CoV-2.