How does SARS CoV-2 infect blood vessels?

People who are severely affected by COVID-19 show symptoms of damage to their blood system, as well as to their lungs. For example, their blood may form lots of clots, which can cause damage to lots of different tissues in the body. Also other tissues than the lungs may be damaged in COVID-19, such as the heart, and it is likely that infection spreads to these tissues through the blood system. It will be important to know how blood vessels are infected by SARS CoV-2, the virus that causes COVID-19, to understand how damage to blood vessels and other tissues occurs. Our research will discover which types of cells in blood vessels become infected with SARS CoV-2, which will help us understand how blood vessels and other tissues become damaged in COVID-19, and suggest which cells to target to prevent this damage. The two most likely cells that might be infected are endothelial cells, which form the inside surface of blood vessels, or pericytes, which form part of the outer wall of very small blood vessels. In our work, we will use a special inactive version of SARS CoV-2 that cannot replicate but will label cells that have taken it up (become infected). We will apply this inactive version of the SARS CoV-2 virus to endothelial cells and pericytes that are grown in a dish, and see which cell type becomes most strongly labelled, indicating that it takes up the virus most strongly. We then want to find out whether the blood vessels are differently infected in different organs, and whether this could explain some of the non-respiratory symptoms that people suffer from. To investigate this, we will use mice. However, SARS CoV-2 does not infect mouse cells, so we will use two approaches. In one set of experiments, we will use genetically altered mice that express the human version of the protein that binds SARS CoV-2. In another set of experiments we will use normal mice and a version of the inactive virus that has a mutation so it binds to the mouse version of the SARS CoV-2 receptor protein. By injecting the inactive virus into the bloodstream of these mice, we will discover which cells the virus infects in different tissues, including the heart and brain. Finally, we want to find out what factors affect the severity of infection with SARS CoV-2. We will test whether existing inflammation makes it easier for SARS CoV-2 to infect blood vessels, by injecting mice with a bacterial protein that triggers an inflammatory response, before injecting the inactive SARS CoV-2 virus. We will also test whether a gene called APOE4, that seems to be linked with severe COVID-19 in humans, increases infection of blood vessels in our experimental mice. Together, our experiments will discover how blood vessels become infected with SARS CoV-2, indicating which cells to target with treatments, and will test whether risk factors for severe COVID-19 illness could act by increasing the ability of SARS CoV-2 to infect cells on blood vessels.