Identification of the Initial Targets of Transmission

识别初始传播目标

• 批准号: 10157877
• 负责人: Thomas Hope
• 金额: $ 78.6万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157877
• 关键词: 2019-nCoV; Active Sites; Adult; Age; Anatomy; Animals; Anti-Retroviral Agents; Antibodies; Autopsy; Blood Vessels; Brain; COVID-19; COVID-19 pandemic; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Clinical Trials; Collaborations; Complex; Coronary artery; Department chair; Development; Diabetes Mellitus; Disease; Emergency Situation; FDA approved; Future; HIV; Homeostasis; Human; Hypertension; Hypoxia; Image; Immune; Immunology; Individual; Infection; Inflammation; Intervention; Intestines; Kidney; Kidney Failure; Knowledge; Label; Laboratories; Liver; Lung Inflammation; Lung diseases; Lung infections; Macaca; Macaca mulatta; Methods; Modeling; Modernization; Monitor; Mucous Membrane; Myocardial Infarction; Natural History; Natural Immunity; Neurons; Normalcy; Organ; Organ failure; PET/CT scan; Pancreas; Pathogenesis; Pathologist; Pathology; Patients; Peptidyl-Dipeptidase A; Pharmacotherapy; Physiology; Play; Pneumonia; Population; Positioning Attribute; Postdoctoral Fellow; Primates; Publications; Published Comment; Radiolabeled; Reporting; Research; Respiration; Respiratory System; Respiratory physiology; Role; SIV; Serine Protease; Signal Transduction; Site; Smell Perception; Social Distance; Stroke; Symptoms; System; TMPRSS2 gene; Taste Perception; Techniques; Temperature; Testing; Testis; Time; Tissues; Toes; Type 2 Angiotensin II Receptor; Uncertainty; United States; Vaccines; Veterinary Pathology; Viral; Viral Load result; Virus; Virus Diseases; Virus Replication; Work; adaptive immunity; base; biosafety level 3 facility; body system; comorbidity; coronavirus disease; cytokine release syndrome; drug candidate; effective therapy; experience; gastrointestinal symptom; improved; in vivo; inhibitor/antagonist; innovation; insight; men; mortality; neutralizing antibody; novel; pandemic disease; parent project; radiotracer; respiratory; respiratory virus; response; sex; therapeutic development; transmission process; uptake; vaccine development; virology

Summary: The current pandemic of COVID-19 has rapidly spread around the world infecting millions and killing more than 200,000 people in just months. The first wave of the pandemic is currently peaking in the United States causing almost 60,000 deaths in the past 6 weeks. This highly contagious virus with the unique features of a high percentage of asymptomatic infected and delayed severe symptoms has wreaked havoc on the population of the US. Without any other options, the US population is flattening the curve by social distancing and self-isolation. To return to normality we need an effective vaccine or therapy to protect populations around the world. Although the SARS-CoV-2 (CoV2) virus is known as a respiratory virus, it clearly has an impact beyond lung infection with increasing evidence of infection influencing multiple organ systems. Unanticipated pathologies associated with CoV2 infection such as heart attacks, loss of taste and smell, kidney failure, stroke, and COVID toe suggest possible virus dissemination beyond the respiratory tract. Such dispersed anatomical infection is possible because the CoV2 receptor ACE2 is expressed in a variety of tissues, tightly regulated by innate and adaptive immunity, and plays a key role in vascular homeostasis. High levels of ACE2 expression in the respiratory tract, liver, kidney, pancreas and cardiovascular tissues correlates with co-morbidities associated with death after extended infection. But to better define COVID-19 pathogenesis, it is essential to determine if these multiple end organ diseases leading to death are an indirect consequence of CoV2 induced inflammation and hypoxia or a consequence of direct CoV2 infection of various tissues and organs. Through the parent project and other work, we have developed the concepts of signal guided necropsies and multiscale imaging to identify and study small foci of SIV replication in the early days after mucosal transmission or rebound after cessation of antiretroviral drug treatment. The best of these methods utilizes radiolabeled and fluorescently tagged antibody- based probes to identify and in vivo fluorescently label SIVmac239 infected cells. In this emergency competitive revision application, we will adapt these novel and innovative techniques to study CoV2 infection. Critically, these state-of-the-art methods to identify active sites of CoV2 at the whole live animal method in an unbiased manner. Knowing the active anatomical sites of virus replication and inflammation will synergize with modern pathology approaches to provide an increased understanding of the natural history and pathogenesis of CoV2 infection. Based on the conceptual and technical innovation described above, combined with the more than 50 years of combined virology research expertise of Drs. Veazey and Hope, we believe the application has great potential to impact and advance the new field of COVID-19 research. This critical basic understanding will inform the field and advance strategies to stop the pandemic. There is no doubt the completion of the studies described in this application will advance the field. And we are currently the only ones in the world that can deliver the described studies at the accelerated pace of research needed for this emergency.

摘要：当前的 COVID-19 大流行已在世界范围内迅速蔓延，感染数百万人并造成死亡 短短几个月内就有超过 200,000 人。目前，第一波疫情在美国正处于高峰期 过去 6 周内，各州造成近 6 万人死亡。这种具有高度传染性的病毒具有独特的特征 高比例的无症状感染者和迟发的严重症状对社会造成了严重破坏 美国人口。在没有任何其他选择的情况下，美国人口正在通过保持社交距离拉平曲线 和自我隔离。为了恢复正常，我们需要有效的疫苗或疗法来保护周围的人群 世界。尽管 SARS-CoV-2 (CoV2) 病毒被称为呼吸道病毒，但它显然具有影响 除了肺部感染之外，越来越多的证据表明感染影响多个器官系统。意外 与 CoV2 感染相关的病症，例如心脏病发作、味觉和嗅觉丧失、肾衰竭、中风、 和新冠脚趾表明病毒可能传播到呼吸道以外。这种分散的解剖结构 感染是可能的，因为 CoV2 受体 ACE2 在多种组织中表达，并受到 先天性和适应性免疫，在血管稳态中发挥关键作用。 ACE2 的高水平表达 呼吸道、肝脏、肾脏、胰腺和心血管组织与相关并发症相关 长期感染后死亡。但为了更好地定义 COVID-19 发病机制，必须确定是否 这些导致死亡的多种终末器官疾病是 CoV2 诱导炎症的间接后果 缺氧或各种组织和器官直接感染 CoV2 的结果。通过父项目 和其他工作中，我们开发了信号引导尸检和多尺度成像的概念来识别 并研究粘膜传播后早期 SIV 复制的小病灶或停止后反弹的情况 抗逆转录病毒药物治疗。这些方法中最好的方法是利用放射性标记和荧光标记的抗体- 基于探针来识别和体内荧光标记 SIVmac239 感染的细胞。在这紧急的竞争中 修订申请后，我们将采用这些新颖和创新的技术来研究 CoV2 感染。关键的是， 这些最先进的方法可以在整个活体动物方法中以公正的方式识别 CoV2 的活性位点 方式。了解病毒复制和炎症的活跃解剖部位将与现代医学相结合 病理学方法可加深对 CoV2 自然史和发病机制的了解 感染。基于上述理念和技术创新，结合50多项 博士多年的综合病毒学研究专业知识。 Veazey 和 Hope，我们相信该应用程序具有出色的性能 影响和推进 COVID-19 研究新领域的潜力。这一关键的基本理解将 为现场提供信息并推进阻止这一流行病的战略。学业完成毫无疑问 本申请中描述的内容将推动该领域的发展。我们是目前世界上唯一能够提供 所描述的研究需要加快这种紧急情况所需的研究速度。