COVID-19 comorbidity studies in Syrian hamster models

叙利亚仓鼠模型中的 COVID-19 合并症研究

基本信息

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
项目类别：
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

项目摘要

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，此外，免疫功能低下的患者也面临严重的风险。 COVID-19 是由 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最近，我们建立了叙利亚仓鼠作为 COVID-19 的稳健动物模型。基于我们对这个模型的研究，我们计划开发和评估糖尿病（目标 1）、肥胖症。（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。将使用高脂肪饮食来产生肥胖仓鼠，用于目标 2 的研究。（“为 COVID-19 研究建立肥胖叙利亚仓鼠”）目标 3 的研究（“有氧运动评估肌病”）。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将通过用以下药物治疗动物来诱导。环磷酰胺（一种常用于诱导免疫抑制的药物）用于目标 4 的研究（“建立用于 COVID-19 研究的免疫功能低下的叙利亚仓鼠”）。（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）将使我们能够监测动物感染 SARS-CoV 的疾病状态。 2、感染后不同时间点测量不同器官的病毒滴度。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，我们还将评估其对共病的敏感性。健康和患有合并症的叙利亚仓鼠再次感染 SARS-CoV-2 此处测试了合并症。导致慢性炎症和/或免疫反应受损，因此，一些亲-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。