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Principal Investigator: MARK L KAHN
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $869,001
Funding agency: National Heart Lung and Blood Institute
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 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.
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corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Secondary to><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Slice><Solid><Specificity><Stiff lung><Testing><Thrombosis><Tissues><Transgenes><Transgenic 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