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Principal Investigator: Thomas Hope
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2020
Award: $786,043
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <2019 novel coronavirus><2019-nCoV><21+ years old><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Active Sites><Adult><Adult Human><Age><Anatomic><Anatomic Sites><Anatomic structures><Anatomical Sciences><Anatomy><Angiotensin AT2 Receptor><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin Receptor 2><Animals><Anti-Retroviral Agents><Antibodies><Antiretroviral Agents><Apoplexy><Autopsy><Autoregulation><BSL-3 facility><BSL3 facility><Blood Vessels><Body Tissues><Brain><Brain Nervous System><Brain Vascular Accident><CD143 Antigens><COVID><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Carboxycathepsin><Cardiac artery><Cardiac infarction><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cessation of life><Clinical Trials><CoV disease><Collaborations><Comment><Commentary><Complex><Coronary artery><Death><Department chair><Development><Diabetes Mellitus><Dipeptidyl Peptidase A><Disease><Disorder><Drug Therapy><Editorial Comment><Emergencies><Emergency Situation><Encephalon><Epitheliasin Gene><FDA approved><Future><Gustation><HIV><Heart Vascular><Heart artery><Homeostasis><Human><Human Immunodeficiency Viruses><Hypertension><Hypoxia><Hypoxic><Image><Immune><Immunes><Immunology><Individual><Infection><Inflammation><Innate Immunity><Intervention><Intervention Strategies><Intestinal><Intestines><Intracellular Communication and Signaling><Kidney><Kidney Failure><Kidney Insufficiency><Kidney Urinary System><Kininase A><Kininase II><Knowledge><LAV-HTLV-III><Label><Laboratories><Liver><Lung Inflammation><Lung diseases><Lung infections><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Methods><Modeling><Modern Man><Modernization><Monitor><Mucosa><Mucosal Tissue><Mucous Membrane><Myocardial Infarct><Myocardial Infarction><Native Immunity><Natural History><Natural Immunity><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Non-Specific Immunity><Nonspecific Immunity><Normalcy><Normalities><Olfaction><Organ><Organ System><Organ failure><Oxygen Deficiency><PET/CT><PET/CT scan><PRSS10><Pancreas><Pancreatic><Pathogenesis><Pathologist><Pathology><Patients><Peptidyl-Dipeptidase A><Pharmacotherapy><Physiological Homeostasis><Physiology><Play><Pneumonia><Population><Position><Positioning Attribute><Postdoc><Postdoctoral Fellow><Primates><Primates Mammals><Publications><Published Comment><Pulmonary Body System><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Organ System><Radiolabeled><Receptor, Angiotensin, Type 2><Renal Failure><Renal Insufficiency><Reporting><Research><Research Associate><Respiration><Respiratory Disease><Respiratory 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processing><gustatory response><heart attack><heart infarct><heart infarction><hepatic body system><hepatic organ system><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><imaging><improved><in vivo><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><insight><interventional strategy><lung disorder><lung function><men><men's><mortality><necropsy><neuronal><neutralizing antibody><novel><odor perception><olfactory perception><pandemic><pandemic disease><parent project><post-doc><post-doctoral><postmortem><pulmonary infections><radiolabel><radiotracer><renal><respiratory><respiratory function><respiratory mechanism><respiratory virus><response><sex><social role><taste processing><taste response><therapeutic agent development><therapeutic development><transmission process><uptake><vaccine development><vaccine formulation><vascular><viral infection><viral multiplication><viral replication><virology><virus infection><virus multiplication><virus-induced 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