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

新冠肺炎疫情突显出，迫切需要更好的诊断病毒感染的方法，以及更好地了解我们的身体是如何对抗它们的。最近，我观察了一组住院的成年患者的血液样本中的所有小分子，这些患者患有不同类型的感染，包括新冠肺炎、其他病毒和细菌。我发现一种特殊的分子，称为‘ddhC’，只在有病毒感染的患者中产生，而在没有病毒感染的患者中很少存在。这引发了几个有趣的问题：A.我们能否使用ddhc来帮助诊断病毒感染？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从两个方面提供帮助：1.在病毒大流行期间，这样一种准备就绪的测试将能够迅速识别和隔离病毒感染者--甚至可以在针对新病毒的特异性测试推出之前使用，帮助立即阻止其传播。我们目前对病毒的检测在准确性和产生结果所需时间方面是有限的。它们也可能需要几周的时间才能形成。由于症状相似，医生目前很难迅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)被过度开出，这会导致细菌对抗生素的耐药性恶化。一种可以快速识别患有病毒而非细菌感染的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。我将调查人体的ddhc产生有何不同：a.仅有轻微不适的患者。感染的早期和晚期。儿童感染，而不是成人感染。细菌和病毒感染同时存在。包括疟疾在内的不同感染，这些调查将使我们了解在广泛的情况下ddhc是如何产生的，并指导其作为诊断工具的潜在使用。目前检测ddhc的方法需要一台名为质谱仪的机器，这需要一个大型实验室，而且运行起来很昂贵。因此，我还将研究是否可以使用适体来检测ddhC，适体是一种小DNA片段，可以潜在地与ddhC等小分子结合并捕获，从而开发出一种更直接的诊断测试，而不依赖于复杂的机制。b.ddhC在病毒感染中的生物学作用是什么？尽管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。它能有效预防病毒感染吗？它在不同感染中的作用是否有所不同？以前在细胞中的研究表明，一种形式的ddhC可以使负责其复制的病毒的特定部分失效。这表明DdhC在病毒感染中具有保护作用，但为了了解更多，我们需要更多数据。我将研究不同病毒感染中人类细胞产生DdhC的水平，包括导致新冠肺炎的SARS-CoV-2病毒的不同变种。然后，我将看看当我们引入外部ddhC时，以及当我们打开和关闭某些负责ddhC生产的基因时，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人体会产生ddhC来应对病毒感染，这可能有助于在未来找到治疗这些感染的新方法。综上所述，我建议的研究将使我们更好地理解ddhC在病毒感染的诊断和生物反应中的作用，这将有助于我们与病毒疾病和日益恶化的抗生素耐药性作斗争。

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.