Intravital imaging of COVID-19 lungs to visualize pathogenic differences between SARS-CoV-2 variants of concern

One of the most enigmatic features of SARS-CoV-2 infection is the clinical observation that some individuals have a mild infection that does not require any medical treatment, while others develop severe Coronavirus Disease (COVID) that results in hospitalization and even death. Doctors and scientists are guessing at what causes severe COVID. We propose to look inside the body to elucidate this issue. Our team is comprised of Dr. Corcoran, uniquely an endothelial cell virologist, Dr Braedon McDonald an ICU doctor that takes care of COVID patients and Dr. Kubes, an immunologist and one of the few investigators worldwide capable of visualizing active immune responses after lung infection in living animals. Our combination of expertise will permit us to mutate or fluorescently tag SARS-CoV-2 variants in order to watch the virus as it infects the animal or human blood vessels. It is our believe the lining of blood vessels gets infected. We can color-code each immune cell, visualize blood vessels, and witness the virus-host battle in real time using imaging. We now plan to extend our initial studies on an early isolate of SARS-CoV-2 to the variants of concern. We have a clinical source for patient isolates of SARS-CoV-2 variants, in order to compare how immune responses and disease course including the long haul effects may differ in these infections compared to the 'original' SARS-CoV-2 strain. We will use the SARS-CoV-2 infectious clone that turns cells green after it infects them to track the course of the virus and variants in live animals and human vessels. With these tools and protocols in place, and our functional CL3 facility, our group is poised to make important observations about how the variants of concern may alter the course of infection and the immune response that will complement clinical data. Finally, we have a number of potential therapeutic targets (one of which is in phase 2 clinical trials) to test efficacy in infections with the various variants.