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.

综述：当前新冠肺炎大流行已迅速蔓延全球数百万人感染并致死 在短短几个月内就有20多万人。第一波大流行目前正在美国达到顶峰 在过去的6周里，该州造成了近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和延迟的严重症状对 美国的人口。在没有其他选择的情况下，美国人正在通过社交距离来拉平这一曲线 和自我孤立。为了恢复正常，我们需要一种有效的疫苗或疗法来保护周围的人口 整个世界。尽管SARS-CoV-2(CoV2)病毒被称为呼吸道病毒，但它显然具有 除肺部感染外，越来越多的证据表明感染影响到多个器官系统。出乎意料的 与CoV2感染相关的病理，如心脏病发作、味觉和嗅觉丧失、肾功能衰竭、中风、 和COVID TOE表明病毒可能在呼吸道以外传播。如此分散的解剖结构 感染是可能的，因为CoV2受体ACE2在各种组织中表达，受 先天免疫和获得性免疫，在血管内稳态中起着关键作用。血管紧张素转换酶2的高水平表达 呼吸道、肝脏、肾脏、胰腺和心血管组织与相关的合并症相关 在广泛感染后死亡。但为了更好地定义新冠肺炎的发病机制，至关重要的是确定 这些导致死亡的多器官疾病是CoV2诱导的炎症的间接后果 以及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，我们发展了信号引导尸检和多尺度成像的概念来识别 并研究SIV在黏膜传播后早期的小病灶复制或停止后反弹 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- 基于探针识别并在体内荧光标记SIVmac239感染细胞。在这种紧急情况下竞争 修订应用，我们将采用这些新的和创新的技术来研究CoV2感染。关键是， 这些最先进的方法在整个活体动物中识别CoV2的活性部位的方法没有偏见 举止。了解病毒复制和炎症的活跃解剖部位将与现代 病理学方法提供对CoV2自然病史和发病机制的更多了解 感染。基于上述概念和技术创新，结合50多家 结合Veazey博士和Hope博士多年的病毒学研究专业知识，我们相信这种应用程序具有很好的应用前景 有潜力冲击和推进新冠肺炎研究的新领域。这一关键的基本理解将 向实地通报情况，并推进阻止大流行的战略。毫无疑问，这些研究已经完成了 本申请中描述的内容将推动该领域的发展。而我们目前是世界上唯一能够提供 所描述的研究加快了这一紧急情况所需的研究步伐。