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SARS-COV-2（严重的急性呼吸综合征冠状病毒2）病毒会引起严重，并且 甚至在某些患者中，即使是致命感染，主要患有合并症，例如高血压，糖尿病，糖尿病， 肥胖和心血管疾病。此外，免疫功能低下的患者也有严重的高风险 Covid-19，该疾病由SARS-COV-2引起。动物模型对于预防性测试和 COVID-19的治疗方法，但模型概括了与之相关的主要合并症 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 研究。在我们的工作中，我们在这里计划开发和评估糖尿病患者（AIM 1），肥胖 （AIM 2），心肌病（AIM 3）和免疫功能低下（AIM 4）叙利亚仓鼠进行COVID-19。 对于AIM 1（“评估糖尿病叙利亚仓鼠进行COVID-19研究”），我们已经证明了我们的 通过用链蛋白酶治疗糖尿病仓鼠来产生糖尿病的汉仓的能力，这种药物通常用于 建立糖尿病动物模型。高脂饮食将用于在AIM 2中产生肥胖的仓鼠进行研究 （“建立肥胖的叙利亚仓鼠进行Covid-19研究”）。 AIM 3的研究（'评估心肌疗法 Covid-19研究的叙利亚仓鼠将与Bio14.6叙利亚仓鼠进行，这是一个已建立的 心肌病模型。通过治疗动物 环磷酰胺（一种通常用于诱导免疫抑制的药物）进行AIM 4（建立 免疫功能低下的叙利亚仓鼠进行了COVID-19研究”。特定标记，例如血糖水平 （对于糖尿病），瘦素水平（肥胖），肌钙蛋白T水平（心血管损伤）和白细胞计数（用于 免疫抑制）将使我们能够监测疾病状态。然后，动物将被SARS-COV感染 2，不同器官中的病毒滴度将在感染后在不同的时间点进行测量。此外，我们将 测量病毒脱落的持续时间和病毒传播的效率，这两者都可以增加 与健康的SARS-COV-2感染动物相比，在合并期间。我们还将评估 用健康和合并症叙利亚仓鼠的SARS-COV-2重新感染。这里测试的合并症 导致慢性炎症和/或免疫反应受损。因此，几个促进的水平 将评估这些仓鼠血清样品中SARS-COV-2的炎性细胞因子和抗体。 总的来说，我们将建立并测试一些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叙利亚仓鼠模型提供一个可靠的平台 和SARS-COV-2的抗病毒化合物。