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大流行病已在世界各地迅速蔓延，感染了数百万人并造成死亡 短短几个月就有超过20万人死亡大流行的第一波目前在美国达到高峰， 在过去的六周里造成了近6万人死亡。这种传染性极强的病毒 高比例的无症状感染者和迟发性严重症状已经严重破坏了 美国的人口。在没有其他选择的情况下，美国人口正在通过社交距离来拉平曲线 自我隔离。为了恢复正常，我们需要一种有效的疫苗或治疗方法来保护周围的人群。 世界尽管SARS-CoV-2（CoV 2）病毒被称为呼吸道病毒，但它显然对 随着感染影响多个器官系统的证据越来越多，非预期 与CoV 2感染相关的病理，例如心脏病发作、味觉和嗅觉丧失、肾衰竭、中风， 和COVID脚趾表明病毒可能传播到呼吸道以外。如此分散的解剖结构 感染是可能的，因为CoV 2受体ACE 2在多种组织中表达，受 先天性和适应性免疫，并在血管稳态中起关键作用。ACE 2高水平表达， 呼吸道、肝脏、肾脏、胰腺和心血管组织与相关的合并症相关 感染时间延长后死亡但为了更好地定义COVID-19的发病机制，必须确定 这些导致死亡的多个终末器官疾病是CoV 2诱导的炎症的间接后果 和缺氧或各种组织和器官的直接CoV 2感染的结果。通过父项目 和其他工作，我们已经开发了信号引导尸检和多尺度成像的概念，以确定 并研究粘膜传播后早期SIV复制的小病灶或停止传播后的反弹。 抗逆转录病毒药物治疗这些方法中最好的是利用放射性标记和荧光标记的抗体- 的探针来鉴定和体内荧光标记SIVmac 239感染的细胞。在这种紧急竞争中， 修订申请，我们将采用这些新的和创新的技术来研究CoV 2感染。关键是， 这些最先进的方法以无偏的方式在整个活动物方法中鉴定CoV 2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协同作用。 病理学方法，以增加对CoV 2自然史和发病机制的了解 感染基于上述概念和技术创新，结合50多个 Veazey博士和Hope博士多年的病毒学研究专长，我们相信该应用具有巨大的 影响和推进新冠肺炎研究新领域的潜力。这一重要的基本认识将 向实地通报情况，并推进制止这一流行病的战略。毫无疑问，研究的完成 本申请中所描述的将推进该领域。我们是目前世界上唯一能提供 所述的研究加快了应对这一紧急情况所需的研究步伐。