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.

项目摘要 大流行性SARS-CoV-2（严重急性呼吸综合征冠状病毒2）病毒可引起严重和 甚至在一些患者中，主要是那些患有合并症如高血压，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风险 COVID-19，由SARS-CoV-2引起的疾病。动物模型对于预防和治疗的测试至关重要。 COVID-19的治疗方法，但概括与COVID-19相关的主要合并症的模型 COVID-19缺乏。最近，我们建立了叙利亚仓鼠作为COVID-19的强大动物模型 research.基于我们对该模型的研究，我们计划开发和评估糖尿病（目标1），肥胖 (Aim 2）、心肌病（Aim 3）和免疫功能低下（Aim 4）的叙利亚仓鼠进行COVID-19研究。 对于目标1（“评估糖尿病叙利亚仓鼠用于COVID-19研究”），我们已经证明了我们的 通过用链脲佐菌素治疗叙利亚仓鼠，这种药物通常用于治疗糖尿病， 建立糖尿病动物模型。高脂肪饮食将用于产生肥胖仓鼠，用于Aim 2的研究 （“为COVID-19研究建立肥胖的叙利亚仓鼠”）。目标3中的研究（“评估心肌病 叙利亚仓鼠进行COVID-19研究“）将与BIO14.6叙利亚仓鼠进行，BIO14.6叙利亚仓鼠是一种已建立的 心肌病模型。免疫受损状态将通过用以下物质处理动物来诱导： 环磷酰胺（一种常用于诱导免疫抑制的药物），用于目标4（“建立 免疫受损的叙利亚仓鼠用于COVID-19研究“）。特异性标志物，如血糖水平 (for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）将允许我们监测疾病状态。然后动物将感染SARS-CoV， 2，并在感染后的不同时间点测量不同器官中的病毒滴度。此外，我们会 测量病毒脱落的持续时间和病毒传播的效率，两者都可能增加 与健康SARS-CoV-2感染动物相比，我们还将评估 再次感染SARS-CoV-2的健康和共病叙利亚仓鼠。这里检测的合并症 导致慢性炎症和/或免疫应答受损。因此，几个亲- 将评估来自这些仓鼠的血清样品中的炎性细胞因子和SARS-CoV-2抗体。 我们将共同建立和测试几种叙利亚仓鼠共病模型用于SARS-CoV-2研究。 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 和抗SARS-CoV-2病毒化合物。