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Principal Investigator: JASON S DEBLEY
Organization: SEATTLE CHILDREN'S HOSPITAL
Fiscal Year: 2020
Award: $193,352
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
This application is an Emergency Competitive Revision (PA-20-135) to existing NIH award K24AI150991
proposing immediate work to help address the urgent need for research on Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19). While the majority of
cases of COVID19 result in mild symptoms, some progress to respiratory and multi-organ failure. The case
fatality rate for COVID19 varies widely according to age group and underlying medical comorbidities. There an
urgent need to improve our understanding of mechanisms that underlie the heterogeneity of disease severity
with SARS-CoV2 infection between individuals and explain why children are more resistant to developing
severe COVID-19 than adults. Such knowledge will be critical in developing novel therapeutic interventions to
treat and prevent SARS-CoV2 infection and COVID19 disease. One theory for the widely varying COVID-19
disease severity between children and adults, and even between older adults, is heterogeneity between
individuals in how the virus gains entry to airway epithelial cells (AECs). The spike protein of SARS CoV2 uses
angiotensin converting enzyme 2 (ACE-2) as its cell binding site and the membrane serine protease TMPRSS2
primes the spike protein. In humans it is unknown if epithelial expression of ACE-2 or TMPRSS2 are lower
among children as compared to adults. In animals two common antihypertension medications (angiotensin II
receptor blockers, ARBs; and angiotensin-converting-enzyme inhibitors, AECi) increase ACE-2 expression,
fueling debate about the effect of these drugs on the infectivity of SARS-CoV2 and risk of COVID-19. We
recently observed that ACE-2 expression by bronchial AECs from children increases following infection with
human rhinovirus, prompting us to question whether a recent rhinovirus infection modulates SARS-CoV2
infection and the risk of COVID-19. The first aim of this Competitive Revision is to determine whether bronchial
AEC expression of ACE-2 varies with age or pre-infection with human rhinovirus, and whether treatment of
AECs with ARBs, ACEi or exogenous ACE-2, modulate SARS CoV2 infectivity and replication. A second
potential explanation for varying COVID-19 disease severity is heterogeneity in type I and III interferon (IFN
I/III) responses between individuals to SARS-CoV2. The second aim of this Competitive Revision, which
logically extends from the goals of the applicant’s parent award (K24AI150991), is to determine if heterogeneity
of AEC IFN I/III responses following SARS-CoV2 infection of primary AECs from children and adults is
associated with viral replication, and whether the drug azithromycin increases AEC IFN I/III responses to
SARS-CoV2 and reduces viral replication. Finally, this supplement to K24AI150991 will also support the direct
mentorship of 3 junior faculty physician-scientists and a PhD candidate who are all engaged in mechanistic
COVID-19 patient-oriented research under the applicant’s mentorship or co-mentorship.
Terms: <0-11 years old><2019 novel coronavirus><2019-nCoV><21+ years old><ACE Inhibitors><Address><Adult><Adult Human><Age><Air><Alleles><Allelomorphs><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin I-Converting Enzyme Inhibitors><Angiotensin II Receptor><Angiotensin Receptor><Angiotensin-Converting Enzyme Antagonists><Angiotensin-Converting Enzyme Inhibitors><Angiotensins><Animals><Award><Azadose><Azithromycin><Azitrocin><Azythromycin><BSL-3 facility><BSL3 facility><Binding><Binding Proteins><Binding Sites><CD143 Antigens><COVID-19><COVID19><Carboxycathepsin><Case Fatality Rates><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cell Body><Cell Line><CellLine><Cells><Cessation of life><Child><Child Youth><Children (0-21)><Combining Site><Complex><Coronaviridae><Coronavirus><Data><Death><Dipeptidyl Peptidase A><Disease><Disorder><Doctor of Philosophy><Drugs><Elderly><Emergencies><Emergency Situation><Environment><Epithelial><Epithelial Cells><Epitheliasin Gene><Epithelium><Epithelium Part><Faculty><Failure><Goals><HCoV><Heterogeneity><Human><IFN><Incidence><Individual><Infection><Infection prevention><Interferons><Investigators><K24 Award><Kininase A><Kininase II><Kininase II Antagonists><Kininase II Inhibitors><Knowledge><Laboratories><Ligand Binding Protein><Ligand Binding Protein Gene><Liquid substance><Lung diseases><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Medical><Medication><Membrane><Mentorship><Mice><Mice Mammals><Mid-Career Clinical Scientist Award (K24)><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Minor><Modeling><Modern Man><Molecular Interaction><Murine><Mus><NIH><National Institutes of Health><Non-Polyadenylated RNA><PRSS10><Parents><Pathogenicity><Peptidyl-Dipeptidase A><Ph.D.><PhD><Pharmaceutic Preparations><Pharmaceutical Preparations><Physicians><Population><Position><Positioning Attribute><Prevent infection><Primary Infection><Production><Protein Binding><Proteins><Publishing><Pulmonary Diseases><Pulmonary Disorder><RNA><RNA Gene Products><Reactive Site><Receptor Protein><Recombinants><Research><Research Personnel><Research Resources><Researchers><Resistance><Resources><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Rhinovirus><Rhinovirus infection><Ribonucleic Acid><Risk><SARS><SARS Virus><SARS corona virus><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Scientist><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe acute respiratory syndrome coronavirus 2><Severities><Severity of illness><Strains Cell Lines><Surface><Symptoms><TMPRSS2><TMPRSS2 gene><Testing><Therapeutic Intervention><Tracheobronchial><Training><Ultreon><United States National Institutes of Health><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus Replication><Work><Wuhan coronavirus><Zithromax><Zitromax><adulthood><advanced age><age group><ages><airway epithelium><alleviate symptom><ameliorating symptom><animal data><biosafety level 3 facility><bound protein><children><childrens'><co-morbid><co-morbidity><comorbidity><corona virus><corona virus disease 2019><coronavirus disease 2019><cultured cell line><decrease symptom><disease heterogeneity><disease of the lung><disease severity><disorder of the lung><drug/agent><elders><fewer symptoms><fluid><geriatric><human CoV><human corona virus><human coronavirus><improved><infected with Rhinovirus><infection rate><infection risk><intervention therapy><late life><later life><liquid><loss of function><lung disorder><membrane structure><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel therapeutic approach><novel therapeutic intervention><novel therapy approach><older adult><older person><patient oriented research><patient oriented study><prevent><preventing><rate of infection><receptor><reduce symptoms><relieves symptoms><resistant><respiratory><respiratory virus><response><senior citizen><severe acute respiratory syndrome-CoV><symptom alleviation><symptom reduction><symptom relief><theories><viral multiplication><viral replication><virus multiplication><virus protein><youngster>