How does SARS CoV-2 infect blood vessels?

受COVID-19严重影响的人会表现出血液系统受损的症状，以及肺部受损的症状。例如，他们的血液可能会形成大量的凝块，这可能会对身体中的许多不同组织造成损害。此外，肺部以外的其他组织也可能在COVID-19中受损，例如心脏，并且感染很可能通过血液系统传播到这些组织。重要的是要知道血管是如何被SARS CoV-2（导致COVID-19的病毒）感染的，以了解血管和其他组织的损伤是如何发生的。我们的研究将发现血管中哪些类型的细胞会感染SARS CoV-2，这将有助于我们了解血管和其他组织如何在COVID-19中受损，并建议针对哪些细胞来预防这种损伤。最有可能被感染的两种细胞是内皮细胞，它形成血管的内表面，或者周细胞，它形成非常小的血管的外壁的一部分。在我们的工作中，我们将使用一种特殊的非活性SARS CoV-2，它不能复制，但会标记已经吸收它（被感染）的细胞。我们将把这种非活性的SARS CoV-2病毒应用于培养皿中生长的内皮细胞和周细胞，看看哪种细胞类型的标记最强烈，表明它最强烈地吸收病毒。然后，我们想知道血管在不同器官中是否受到不同的感染，以及这是否可以解释人们遭受的一些非呼吸道症状。为了研究这个问题，我们将使用老鼠。然而，SARS CoV-2不会感染小鼠细胞，因此我们将使用两种方法。在一组实验中，我们将使用基因改变的小鼠，这些小鼠表达结合SARS CoV-2的人类蛋白质。在另一组实验中，我们将使用正常小鼠和一种具有突变的失活病毒，使其与SARS CoV-2受体蛋白的小鼠版本结合。通过将失活病毒注射到这些小鼠的血液中，我们将发现病毒感染了包括心脏和大脑在内的不同组织中的哪些细胞。最后，我们想找出影响SARS CoV-2感染严重程度的因素。我们将测试现有的炎症是否会使SARS CoV-2更容易感染血管，方法是在注射非活性SARS CoV-2病毒之前，给小鼠注射一种引发炎症反应的细菌蛋白。我们还将测试一种名为APOE 4的基因是否会增加我们实验小鼠的血管感染，该基因似乎与人类严重的COVID-19有关。总之，我们的实验将发现血管是如何感染SARS CoV-2的，表明治疗的目标细胞，并将测试严重COVID-19疾病的风险因素是否可以通过增加SARS CoV-2感染血管细胞的能力来发挥作用。

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.