PDF(Pubmed)
Abstract：
Diabetes, a prevalent chronic condition, significantly increases the risk of mortality from COVID-19, yet the underlying mechanisms remain elusive. Emerging evidence implicates Cathepsin L (CTSL) in diabetic complications, including nephropathy and retinopathy. Our previous research identified CTSL as a pivotal protease promoting SARS-CoV-2 infection. Here, we demonstrate elevated blood CTSL levels in individuals with diabetes, facilitating SARS-CoV-2 infection. Chronic hyperglycemia correlates positively with CTSL concentration and activity in diabetic patients, while acute hyperglycemia augments CTSL activity in healthy individuals. In vitro studies reveal high glucose, but not insulin, promotes SARS-CoV-2 infection in wild-type cells, with CTSL knockout cells displaying reduced susceptibility. Utilizing lung tissue samples from diabetic and non-diabetic patients, alongside Leprdb/dbmice and Leprdb/+mice, we illustrate increased CTSL activity in both humans and mice under diabetic conditions. Mechanistically, high glucose levels promote CTSL maturation and translocation from the endoplasmic reticulum (ER) to the lysosome via the ER-Golgi-lysosome axis. Our findings underscore the pivotal role of hyperglycemia-induced CTSL maturation in diabetic comorbidities and complications.
People with diabetes are at greater risk of developing severe COVID-19 and dying from the illness, which is caused by a virus known as SARS-CoV-2. The high blood sugar levels associated with diabetes appear to be a contributing factor to this heightened risk. However, diabetes is a complex condition encompassing a range of metabolic disorders, and it is therefore likely that other factors may contribute. Previous research identified a link between an enzyme called cathepsin L and more severe COVID-19 in people with diabetes. Elevated cathepsin L levels are known to contribute to diabetes complications, such as kidney damage and vision loss. It has also been shown that cathepsin L helps SARS-CoV-2 to enter and infect cells. This raised the question of whether elevated cathepsin L is responsible for the increased COVID-19 vulnerability in patients with diabetes. To investigate, He, Zhao et al. monitored disease severity and cathepsin L levels in patients with COVID-19. This confirmed that people with diabetes had more severe COVID-19 and that higher levels of cathepsin L are linked to more severe disease. Analysis also revealed that cathepsin L activity increases as blood glucose levels increase. In laboratory experiments, cells exposed to glucose or fluid from the blood of people with diabetes were more easily infected with SARS-CoV-2, with cells genetically modified to lack cathepsin L being more resistant to infection. Further experiments revealed this was due to glucose promoting maturation and migration of cathepsin L in the cells. The findings of He, Zhao et al. help to explain why people with diabetes are more likely to develop severe or fatal COVID-19. Therefore, controlling blood glucose levels in people with diabetes may help to prevent or reduce the severity of the disease. Additionally, therapies targeting cathepsin L could also potentially help to treat COVID-19, especially in patients with diabetes, although more research is needed to develop and test these treatments.
People with diabetes are at greater risk of developing severe COVID-19 and dying from the illness, which is caused by a virus known as SARS-CoV-2. The high blood sugar levels associated with diabetes appear to be a contributing factor to this heightened risk. However, diabetes is a complex condition encompassing a range of metabolic disorders, and it is therefore likely that other factors may contribute. Previous research identified a link between an enzyme called cathepsin L and more severe COVID-19 in people with diabetes. Elevated cathepsin L levels are known to contribute to diabetes complications, such as kidney damage and vision loss. It has also been shown that cathepsin L helps SARS-CoV-2 to enter and infect cells. This raised the question of whether elevated cathepsin L is responsible for the increased COVID-19 vulnerability in patients with diabetes. To investigate, He, Zhao et al. monitored disease severity and cathepsin L levels in patients with COVID-19. This confirmed that people with diabetes had more severe COVID-19 and that higher levels of cathepsin L are linked to more severe disease. Analysis also revealed that cathepsin L activity increases as blood glucose levels increase. In laboratory experiments, cells exposed to glucose or fluid from the blood of people with diabetes were more easily infected with SARS-CoV-2, with cells genetically modified to lack cathepsin L being more resistant to infection. Further experiments revealed this was due to glucose promoting maturation and migration of cathepsin L in the cells. The findings of He, Zhao et al. help to explain why people with diabetes are more likely to develop severe or fatal COVID-19. Therefore, controlling blood glucose levels in people with diabetes may help to prevent or reduce the severity of the disease. Additionally, therapies targeting cathepsin L could also potentially help to treat COVID-19, especially in patients with diabetes, although more research is needed to develop and test these treatments.
摘要：
糖尿病,一种普遍的慢性病，显著增加了COVID-19的死亡风险，但潜在的机制仍然难以捉摸。新的证据表明组织蛋白酶L（CTSL）与糖尿病并发症有关，包括肾病和视网膜病变。我们先前的研究将CTSL确定为促进SARS-CoV-2感染的关键蛋白酶。这里,我们证明糖尿病患者的血液CTSL水平升高，促进SARS-CoV-2感染。慢性高血糖与糖尿病患者的CTSL浓度和活动呈正相关,而急性高血糖会增加健康个体的CTSL活性。体外研究显示高糖，但不是胰岛素，在野生型细胞中促进SARS-CoV-2感染，CTSL敲除细胞显示降低的易感性。利用糖尿病和非糖尿病患者的肺组织样本，与Leprdb/dbmouse和Leprdb/+小鼠一起，我们说明了在糖尿病条件下，人和小鼠的CTSL活性增加。机械上,高葡萄糖水平促进CTSL成熟并通过内质网（ER）-高尔基体-溶酶体轴从内质网（ER）转位到溶酶体。我们的发现强调了高血糖诱导的CTSL成熟在糖尿病合并症和并发症中的关键作用。
糖尿病患者患严重COVID-19并死于这种疾病的风险更大，这是由一种称为SARS-CoV-2的病毒引起的。与糖尿病相关的高血糖水平似乎是导致这种风险增加的因素。然而,糖尿病是一种复杂的疾病，包括一系列代谢紊乱，因此，其他因素可能会有所贡献。先前的研究确定了一种称为组织蛋白酶L的酶与糖尿病患者中更严重的COVID-19之间的联系。已知升高的组织蛋白酶L水平有助于糖尿病并发症。如肾脏损伤和视力丧失。还显示组织蛋白酶L有助于SARS-CoV-2进入并感染细胞。这提出了一个问题，即升高的组织蛋白酶L是否导致糖尿病患者COVID-19脆弱性增加。为了调查，他,赵等人。监测COVID-19患者的疾病严重程度和组织蛋白酶L水平。这证实了糖尿病患者的COVID-19更为严重，组织蛋白酶L水平越高，疾病越严重。分析还显示组织蛋白酶L活性随着血糖水平的增加而增加。在实验室实验中,糖尿病患者血液中暴露于葡萄糖或液体的细胞更容易感染SARS-CoV-2，而经过基因修饰而缺乏组织蛋白酶L的细胞对感染的抵抗力更强。进一步的实验表明，这是由于葡萄糖促进了细胞中组织蛋白酶L的成熟和迁移。他的发现,赵等人。这有助于解释为什么糖尿病患者更容易患上严重或致命的COVID-19。因此,控制糖尿病患者的血糖水平可能有助于预防或减轻疾病的严重程度。此外,针对组织蛋白酶L的治疗也可能有助于治疗COVID-19，特别是在糖尿病患者中，尽管需要更多的研究来开发和测试这些治疗方法。
糖尿病患者患严重COVID-19并死于这种疾病的风险更大，这是由一种称为SARS-CoV-2的病毒引起的。与糖尿病相关的高血糖水平似乎是导致这种风险增加的因素。然而,糖尿病是一种复杂的疾病，包括一系列代谢紊乱，因此，其他因素可能会有所贡献。先前的研究确定了一种称为组织蛋白酶L的酶与糖尿病患者中更严重的COVID-19之间的联系。已知升高的组织蛋白酶L水平有助于糖尿病并发症。如肾脏损伤和视力丧失。还显示组织蛋白酶L有助于SARS-CoV-2进入并感染细胞。这提出了一个问题，即升高的组织蛋白酶L是否导致糖尿病患者COVID-19脆弱性增加。为了调查，他,赵等人。监测COVID-19患者的疾病严重程度和组织蛋白酶L水平。这证实了糖尿病患者的COVID-19更为严重，组织蛋白酶L水平越高，疾病越严重。分析还显示组织蛋白酶L活性随着血糖水平的增加而增加。在实验室实验中,糖尿病患者血液中暴露于葡萄糖或液体的细胞更容易感染SARS-CoV-2，而经过基因修饰而缺乏组织蛋白酶L的细胞对感染的抵抗力更强。进一步的实验表明，这是由于葡萄糖促进了细胞中组织蛋白酶L的成熟和迁移。他的发现,赵等人。这有助于解释为什么糖尿病患者更容易患上严重或致命的COVID-19。因此,控制糖尿病患者的血糖水平可能有助于预防或减轻疾病的严重程度。此外,针对组织蛋白酶L的治疗也可能有助于治疗COVID-19，特别是在糖尿病患者中，尽管需要更多的研究来开发和测试这些治疗方法。
