R01HL164929

Genetic investigation of COVID-19 in lung disease - Summary

The COVID-19 pandemic due to the SARS-CoV-2 virus has resulted in millions of deaths worldwide. The majority of COVID-19 deaths are caused by lung disease characterized by alveolar filling and severe hypoxemia.

Descriptive studies of human patients, animal models, and cultured cells have supported numerous pathogenic mechanisms for COVID-19 lung disease, including direct epithelial cell infection, vascular cell infection and thrombosis, and acute respiratory distress syndrome.

Despite intense investigation, these hypotheses remain unproven due to a lack of cellular functional evidence for causality. SARS-CoV-2 infection requires viral binding of the human ACE2 (HACE2) cell surface protein, and wild-type virus cannot bind mouse ACE2.

Existing HACE2-expressing mice either drive disease through non-endogenous transgenes that do not permit conditional analysis or fail to confer severe illness after infection with SARS-CoV-2. Thus, powerful mouse genetic approaches have not yet been harnessed to test COVID-19 pathogenic mechanisms.

To address this gap in knowledge, we have generated new mouse genetic models that (i) express HACE2 from the mouse ACE2 locus at levels sufficient to confer lethal disease and hypoxia like that observed in human patients, (ii) permit Cre-mediated loss of HACE2 expression to functionally identify cells required to confer COVID-19 disease, and (iii) permit Cre-mediated gain of HACE2 expression to functionally identify cells sufficient for COVID-19 disease.

Our preliminary studies identify both epithelial cell infection and vascular disease associated with extensive intravascular thrombosis in the lungs of HACE2 knockin animals. We therefore hypothesize that COVID-19 lung disease arises due to synergistic infection and/or dysfunction of both lung epithelial and lung vascular cells.

To test this central hypothesis, we will (i) use established Cre-expressing transgenes to test the requirement(s) for epithelial and vascular cell types during COVID-19 lung disease, (ii) use lung slice explants from human and HACE2 knockin mouse lungs to map the cells infected by SARS-CoV-2 virus, and (iii) compare acute and chronic lung responses to infection by the influenza and SARS-CoV-2 viruses to identify the pathogenic mechanisms that underlie the exceptional lethality of COVID-19 lung disease.

These studies are expected to yield a functional and integrated understanding of the events that underlie COVID-19 lung disease and provide a solid scientific foundation for the development of novel therapeutic approaches.

Trustees Of The University Of Pennsylvania

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Pennsylvania United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 309% from $922,822 to $3,774,284.