The role of 3'-Deoxy-3',4'-didehydro-cytidine in the host response to viral infections.

3-脱氧-3,4-二脱氢胞苷在宿主对病毒感染的反应中的作用。

• 批准号: MR/W023865/1
• 负责人: Ravi Mehta
• 金额: $ 33.68万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW023865%2F1
• 关键词: role; Deoxy; didehydro; cytidine; host

The COVID-19 pandemic has highlighted an urgent need for better methods of diagnosing viral infections, as well as an improved understanding of how our bodies fight them. I recently looked at all the small molecules in blood samples from a group of adult patients in hospital with different types of infections including COVID-19, other viruses and bacteria. I found that a specific molecule, called 'ddhC', was only produced by patients with viral infections, and was rarely present in those without. This has raised several interesting questions: A. Can we use ddhC to help diagnose viral infections?Understanding to what extent ddhC is produced in different conditions will help better understand what ddhC does in the body, and inform how we might be able to use it as a diagnostic test. A diagnostic test that can rapidly identify patients with viral infections would help in two ways: 1. In a viral pandemic, a test like this that was 'ready and waiting' would enable prompt identification and isolation of people with the viral infection - and could be used even before tests specific for the new virus were rolled out, helping to stop its spread immediately. The current tests we have for viruses are limited in terms of accuracy and how long they take to generate a result. They can also take several weeks to develop.2. It is currently difficult for doctors to rapidly distinguish between patients with viral and bacterial infections, due to the similarities in symptoms. Consequently, antibiotics (which only work on bacterial infections) are overprescribed, which drives worsening bacterial resistance to antibiotics. A test that can quickly identify patients with viral and not bacterial infections would help reduce unnecessary antibiotic prescriptions and stem worsening antibiotic resistance.I will investigate how the body's ddhC production differs in:a. patients who are only mildly unwellb. early versus late timing of infectionc. infections in children as opposed to adultsd. bacterial and viral infections togethere. different infections, including malariaOverall, these investigations will inform our understanding of how ddhC is produced in a wide range of scenarios, and guide its potential use as a diagnostic tool. The current method to detect ddhC requires a machine called a mass spectrometer, which needs a large laboratory and is expensive to run. Therefore, I will also investigate whether we can detect ddhC using aptamers, which are small pieces of DNA that can potentially bind to and capture small molecules like ddhC, leading to development of a more straightforward diagnostic test not reliant on complex machinery.B. What is the biological role of ddhC in viral infections?Although I have detected ddhC in blood samples of patients with viral infections, I do not know its biological role. Does it work to protect against viral infections? Does its role differ in different infections? Previous work in cells has shown that a form of ddhC can act to disable specific parts of a virus responsible for its replication. This suggests that ddhC is protective in viral infections, but to know more we require further data.I will look at the levels of ddhC produced by human cells in different viral infections, including different variants of SARS-CoV-2, the virus that causes COVID-19. I will then look at what happens to viral growth when we introduce external ddhC, and when we switch certain genes responsible for ddhC production on and off. Through these experiments, we will gain a better understanding of why the body produces ddhC in response to viral infections, which may help identify new treatments for these infections in the future.In summary, the research I am proposing will lead to a better understanding of ddhC's role in both the diagnosis of and biological response to viral infections, which will help in our fight against viral diseases and worsening antibiotic resistance.

2019冠状病毒病大流行凸显了我们迫切需要更好的病毒感染诊断方法，以及更好地了解我们的身体如何对抗病毒。我最近研究了一组住院的成年患者血液样本中的所有小分子，这些患者感染了不同类型的感染，包括COVID-19、其他病毒和细菌。我发现一种名为“ddhC”的特殊分子只在病毒感染的患者体内产生，而在没有病毒感染的患者体内很少出现。这就提出了几个有趣的问题：A.我们可以用ddhC来帮助诊断病毒感染吗？了解ddhC在不同条件下产生的程度将有助于更好地了解ddhC在体内的作用，并告知我们如何将其用作诊断测试。一种能够快速识别病毒感染患者的诊断测试将在两个方面有所帮助：在一场病毒大流行中，这样一种“随时待命”的检测方法将能够迅速识别和隔离病毒感染者，甚至可以在推出针对这种新病毒的检测方法之前使用，从而帮助立即阻止其传播。我们目前对病毒的测试在准确性和产生结果所需的时间方面是有限的。它们也可能需要几周的时间来形成。由于症状相似，目前医生很难快速区分病毒感染和细菌感染的患者。因此，抗生素（只对细菌感染有效）被过度使用，导致细菌对抗生素的耐药性恶化。一种能够快速识别病毒感染而非细菌感染患者的测试将有助于减少不必要的抗生素处方，并阻止抗生素耐药性的恶化。我将研究人体的ddhC产生在以下方面的差异：只有轻微不适的病人。感染的早期和晚期。儿童感染与成人感染不同。细菌和病毒一起感染。总的来说，这些调查将使我们了解在各种情况下ddhC是如何产生的，并指导其作为诊断工具的潜在用途。目前检测ddhC的方法需要一种叫做质谱仪的机器，这需要一个大型实验室，而且运行起来很昂贵。因此，我还将研究我们是否可以使用适体检测ddhC，适体是一种小片段的DNA，可以潜在地结合并捕获像ddhC这样的小分子，从而开发出一种更直接的诊断测试，而不依赖于复杂的机器。ddhC在病毒感染中的生物学作用是什么？虽然我在病毒感染患者的血液样本中检测到ddhC，但我不知道它的生物学作用。它能防止病毒感染吗？它在不同感染中的作用不同吗？先前在细胞中的研究表明，一种形式的ddhC可以使病毒负责复制的特定部分失效。这表明ddhC对病毒感染有保护作用，但为了了解更多，我们需要进一步的数据。我将研究不同病毒感染中人类细胞产生的ddhC水平，包括导致COVID-19的SARS-CoV-2病毒的不同变体。然后我会看看当我们引入外部ddhC时，以及当我们打开和关闭负责ddhC产生的某些基因时，病毒生长会发生什么。通过这些实验，我们将更好地了解为什么身体会产生ddhC来应对病毒感染，这可能有助于确定未来治疗这些感染的新方法。总之，我提出的研究将使我们更好地了解ddhC在病毒感染的诊断和生物反应中的作用，这将有助于我们对抗病毒性疾病和日益恶化的抗生素耐药性。