COVID-19 comorbidity studies in Syrian hamster models

叙利亚仓鼠模型中的 COVID-19 合并症研究

• 批准号: 10450889
• 负责人: YOSHIHIRO KAWAOKA
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450889
• 关键词: 2019-nCoV; ACE2; Acute Respiratory Distress Syndrome; Address; Aftercare; Age; Animal Feed; Animal Model; Animals; Antiviral Agents; Blood Glucose; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19 treatment; Cardiac Myocytes; Cardiovascular Diseases; Cells; Cessation of life; Chronic; Cyclophosphamide; Data; Diabetes Mellitus; Disease; Disease Outbreaks; Disease model; Evaluation; Glucose; Hamsters; High Fat Diet; Human; Hypertension; Immune response; Immune system; Immunocompromised Host; Immunosuppression; Impairment; Individual; Infection; Inflammation; Inflammatory; Lead; Leptin; Lower Respiratory Tract Infection; Measures; Mesocricetus auratus; Meta-Analysis; Modeling; Monitor; Multiple Organ Failure; Names; Obesity; Organ; Outcome; Pathogenicity; Patients; Persons; Pharmaceutical Preparations; Predisposition; Prognosis; Research; Respiratory Tract Infections; Risk Factors; SARS coronavirus; SARS-CoV-2 antibody; SARS-CoV-2 infection; Sampling; Serum; Solid; Streptozocin; Test Result; Testing; Therapeutic; Troponin T; Up-Regulation; Viral Drug Resistance; Virus; Virus Diseases; Virus Shedding; White Blood Cell Count procedure; Work; cardiovascular injury; chemokine; chronic infection; comorbidity; cytokine; diabetic; experience; high risk; immunosuppressed; male; mutant; novel; novel coronavirus; novel virus; pandemic disease; receptor; severe COVID-19; sex; vaccine evaluation; viral transmission

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.

项目概要 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 一些患者甚至会出现致命的感染，主要是患有高血压、糖尿病等合并症的患者， 肥胖、心血管疾病。此外，免疫功能低下的患者也面临严重的高风险。 COVID-19，由 SARS-CoV-2 引起的疾病。动物模型对于预防和测试至关重要 COVID-19 的治疗方法，但概括了与 COVID-19 相关的主要合并症的模型 缺乏 COVID-19。最近，我们建立了叙利亚仓鼠作为 COVID-19 的稳健动物模型 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 （目标 2）、心肌病（目标 3）和免疫功能低下（目标 4）叙利亚仓鼠用于 COVID-19 研究。 对于目标 1（“评估患有糖尿病的叙利亚仓鼠以进行 COVID-19 研究”），我们已经展示了我们的 通过用链脲佐菌素（一种常用来治疗糖尿病的药物）治疗叙利亚仓鼠，能够培育出患有糖尿病的仓鼠。 建立糖尿病动物模型。高脂肪饮食将用于培育肥胖仓鼠，用于目标 2 的研究 （“建立肥胖叙利亚仓鼠用于 COVID-19 研究”）。目标 3 的研究（“评估心肌病 用于 COVID-19 研究的叙利亚仓鼠”）将使用 BIO14.6 叙利亚仓鼠进行，这是一个已建立的 心肌病模型。通过用以下药物治疗动物将诱导免疫受损状态 环磷酰胺（一种常用于诱导免疫抑制的药物）用于目标 4 的研究（“建立 免疫功能低下的叙利亚仓鼠用于 COVID-19 研究”）。特定标志物，例如血糖水平 （对于糖尿病）、瘦素水平（对于肥胖）、肌钙蛋白 T 水平（对于心血管损伤）和白细胞计数（对于 免疫抑制）将使我们能够监测疾病状态。然后动物就会感染 SARS-CoV- 2、感染后不同时间点测量不同器官的病毒滴度。此外，我们将 测量病毒脱落的持续时间和病毒传播的效率，两者都可能会增加 与健康的 SARS-CoV-2 感染动物相比，存在共病。我们还将评估对以下情况的敏感性 健康和患有共病的叙利亚仓鼠再次感染 SARS-CoV-2。此处测试的合并症 导致慢性炎症和/或免疫反应受损。因此，几个亲的水平 将评估这些仓鼠血清样本中的炎症细胞因子和 SARS-CoV-2 抗体。 我们将共同建立并测试几种用于 SARS-CoV-2 研究的叙利亚仓鼠合并症模型。 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。