How does SARS CoV-2 infect blood vessels?

SARS CoV-2 如何感染血管？

• 批准号: MR/V036750/1
• 负责人: Catherine Hall
• 金额: $ 30.09万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV036750%2F1
• 关键词: How; does; SARS; CoV; infect

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.

受新冠肺炎严重影响的人会出现血液系统和肺部受损的症状。例如，他们的血液可能会形成大量凝块，这可能会对体内许多不同的组织造成损害。此外，新冠肺炎还可能损害肺以外的其他组织，如心脏，感染很可能通过血液系统传播到这些组织。了解引起新冠肺炎的SARS CoV-2病毒是如何感染血管的，了解血管和其他组织是如何受到损害的，这一点非常重要。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新冠肺炎中血管和其他组织是如何受到损害的，并建议以哪些细胞为目标来防止这种损害。最有可能被感染的两种细胞是构成血管内表面的内皮细胞，或构成非常小血管外壁一部分的周细胞。在我们的工作中，我们将使用一种特殊的非活跃版本的SARS CoV-2，它不能复制，但会标记已经感染它的细胞。我们将把这种SARS CoV-2病毒的灭活版本应用于培养皿中培养的内皮细胞和周细胞，并观察哪种细胞类型的标记最强，这表明它对病毒的吸收最强。然后我们想要找出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。为了研究这一点，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，我们将使用转基因小鼠，表达与SARS CoV-2结合的蛋白质的人类版本。在另一组实验中，我们将使用正常小鼠和一种具有突变的非活性病毒，使其与小鼠版本的SARS CoV-2受体蛋白结合。通过将灭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使SARS CoV-2更容易感染血管，方法是在注射灭活的SARS CoV-2病毒之前，给小鼠注射一种触发炎症反应的细菌蛋白。我们还将测试一种名为载脂蛋白4的基因是否会增加实验小鼠的血管感染。这种基因似乎与人类严重的新冠肺炎有关。我们的实验将共同发现血管是如何感染SARS CoV-2的，从而指明治疗的目标细胞，并将测试严重新冠肺炎疾病的风险因素是否会通过增加SARS CoV-2感染血管细胞的能力来发挥作用。

项目成果

Choice of method of place cell classification determines the population of cells identified

位置细胞分类方法的选择决定了所识别的细胞群

• DOI: 10.1101/2021.02.26.433025
• 发表时间: 2021
• 作者: Grijseels D

The Emergence of a Stable Neuronal Ensemble from a Wider Pool of Activated Neurons in the Dorsal Medial Prefrontal Cortex during Appetitive Learning in Mice

• DOI: 10.1523/jneurosci.1496-19.2019
• 发表时间: 2020-01-08
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Brebner, Leonie S.;Ziminski, Joseph J.;Koya, Eisuke
• 通讯作者: Koya, Eisuke

Extinction of cue-evoked food-seeking recruits a GABAergic interneuron ensemble in the dorsal medial prefrontal cortex of mice.

线索诱发的食物寻求消失会在小鼠背内侧前额叶皮层中招募 GABA 能中间神经元群。

• DOI: 10.1111/ejn.14754
• 发表时间: 2020
• 期刊: The European journal of neuroscience
• 作者: Brebner LS

An Open-Source Pipeline for Analyzing Changes In Microglial Morphology

用于分析小胶质细胞形态变化的开源流程

• DOI: 10.1101/2021.01.12.426422
• 发表时间: 2021
• 作者: Clarke D

Long COVID: Mechanismen, Risikofaktoren und Genesung

• DOI: 10.1159/000529939
• 发表时间: 2023-03-20
• 期刊: Kompass Pneumologie