[论文解读] The modelling of COVID19 pathways sheds light on mechanisms, opportunities and on controversial interpretations of medical treatments. v2

Maria Luisa Chiusano|arXiv (Cornell University)|Mar 25, 2020

Computational Drug Discovery Methods参考文献 57被引用 12

一句话总结

本文提出了一套以肾素-血管紧张素系统（RAS）为核心的系统生物学模型，用于解释SARS-CoV-2感染机制，将病毒通过ACE2受体进入细胞的过程与疾病发生机制相联系。通过整合已知的分子通路，该模型阐明了关于ACE抑制剂和ARBs在疾病严重程度中作用的争议性问题，以及性别差异的生物学基础，为靶向治疗策略和诊断提供了框架。

ABSTRACT

The new coronavirus (2019-nCoV or SARS-CoV2), inducing the current pandemic disease (COVID-19) and causing pneumoniae in humans, is dramatically increasing in epidemic scale since its first appearance in Wuhan, China, in December 2019. The first infection from epidemic coronaviruses in 2003 fostered the spread of an overwhelming amount of related scientific efforts. The manifold aspects that have been raised, as well as their redundancy offer precious information that has been underexploited and needs to be critically re-evaluated, appropriately used and offered to the whole community, from scientists, to medical doctors, stakeholders and common people. These efforts will favour a holistic view on the comprehension, prevention and development of strategies (pharmacological, clinical etc) as well as common intervention against the new coronavirus spreading. Here we describe a model that emerged from our analysis that was focused on the Renin Angiotensin System (RAS) and the possible routes linking it to the viral infection. because the infection is mediated by the viral receptor on human cell membranes Angiotensin Converting Enzyme (ACE2), which is a key component in RAS signalling. The model depicts the main pathways determining the disease and the molecular framework for its establishment, and can help to shed light on mechanisms involved in the infection. It promptly gives an answer to some of the controversial, and still open, issues concerning predisposing conditions and medical treatments that protect from or favour the severity of the disease (such as the use of ACE inhibitors or ARBs/sartans), or to the sex related biases in the affected population. The model highlights novel opportunities for further investigations, diagnosis and appropriate intervention to understand and fight COVID19.

研究动机与目标

• 将关于SARS-CoV-2感染及肾素-血管紧张素系统（RAS）的现有知识整合为一个统一的分子模型。
• 解决在合并症患者中使用ACE抑制剂和ARBs所引发的争议。
• 解释COVID-19严重程度中性别差异的生物学基础。
• 识别新型分子靶点和干预节点，以推动治疗药物的开发。
• 为临床医生、研究人员及公共卫生决策者提供一个系统层面的框架，以指导疫情期间的决策。

提出的方法

• 构建以肾素-血管紧张素系统（RAS）为核心调控网络的通路模型。
• 将SARS-CoV-2通过人类细胞膜上ACE2受体介导的病毒入侵机制整合进RAS信号级联。
• 绘制SARS-CoV-2、ACE2与下游RAS组分（如血管紧张素II、缓激肽、炎症介质等）之间的关键分子相互作用图谱。
• 利用现有实验和临床数据验证模型预测结果，涵盖合并症、药物效应及性别差异。
• 应用系统生物学原理，通过计算机模拟预测疾病进展及治疗干预的影响。
• 与2003年SARS-CoV的研究结果交叉比对，以指导SARS-CoV-2的致病机制和治疗反应分析。

实验结果

研究问题

• RQ1 SARS-CoV-2如何利用ACE2受体启动感染并扰乱RAS通路？
• RQ2 ACE抑制剂和ARBs在COVID-19患者中产生保护或有害效应的机制基础是什么？
• RQ3 为何男性在COVID-19中的易感性和严重程度高于女性？
• RQ4 RAS网络中的哪些分子节点是最具前景的治疗干预靶点？
• RQ5 如何将关于RAS和病毒致病机制的现有知识整合为可预测的临床决策模型？

主要发现

• 该模型表明，SARS-CoV-2与ACE2结合可导致ACE2下调，破坏RAS的保护性轴，从而通过血管紧张素II积累促进炎症反应。
• 该模型解释了为何ACE抑制剂和ARBs可能不会加重疾病严重程度，甚至可能通过上调ACE2表达而发挥保护作用。
• 性别差异的机制基础在于女性基础ACE2表达水平较高，且雌激素对RAS具有调节作用。
• 该模型识别出缓激肽风暴和内皮 dysfuncion 为重症病例中急性呼吸窘迫综合征（ARDS）的关键驱动因素。
• 以RAS为中心的框架为高血压和糖尿病等合并症作为严重结局危险因素提供了系统层面的解释。
• 该模型突出了潜在的治疗靶点，包括ACE2调节、血管紧张素II受体调控及激肽通路干预，为未来药物开发提供方向。