Uncovering the essential role of host hetero-hexameric ATPases in rhinovirus replication

鼻病毒是大多数普通感冒的罪魁祸首，每年在全球造成数十亿人感染。尽管鼻病毒感染与巨大的健康、经济和社会成本相关，但目前还没有批准的针对鼻病毒的抗病毒药物或疫苗。到目前为止，已经发现了大约170种不同的鼻病毒，迄今为止，所有制造有效疫苗的努力都失败了。试图制造直接针对这种病毒的抗病毒药物也没有效果，部分原因是鼻病毒非常容易变异，并迅速产生耐药性。由于鼻病毒需要进入宿主细胞并与宿主细胞相互作用才能繁殖，因此制造抗病毒药物的新策略可能是针对病毒与宿主细胞之间的相互作用，而不是针对病毒本身。对于这种抗病毒策略，我们首先需要了解病毒如何与宿主细胞相互作用并利用它们进行繁殖。对于鼻病毒，以及许多相关的致病性病毒，如脊髓灰质炎病毒，这一研究领域仍未得到很好的理解。因此，这一领域的任何发现都有望帮助我们了解其他相关病毒，这些病毒通常使用类似的机制与宿主细胞相互作用以进行繁殖。该项目将研究鼻病毒与宿主细胞相互作用的各个方面，这些方面从未被研究过。这个令人兴奋的项目建立在先前由医学研究基金会和哮喘英国资助的项目的基础上。为了在宿主细胞中繁殖，鼻病毒在细胞内繁殖，它们感染一些病毒工厂，在那里产生新的病毒。这些病毒工厂包含一些病毒蛋白质和一些被病毒蛋白质劫持的人类蛋白质，以帮助它们产生新的病毒。虽然我们知道哪些病毒蛋白参与其中，但我们仍然不知道所有被劫持并使病毒繁殖的人类蛋白。在我们之前的项目中，我们已经确定了一些与病毒蛋白有物理接触的宿主蛋白。特别是，其中两种似乎是病毒繁殖所必需的。通过将它们从细胞中移除或用化学物质阻断它们，病毒就不能再繁殖了。这一发现非常令人兴奋，从长远来看，可能会导致新的策略来阻止病毒在宿主细胞中的增殖。但我们首先需要非常详细地了解这些宿主蛋白是如何允许病毒繁殖的。本项目将对此进行调查。在病毒繁殖的不同步骤中，我们将检查哪些病毒需要我们确定的宿主蛋白质。我们将精确分析哪些病毒蛋白与我们发现的宿主蛋白结合，以及这些相互作用是如何发生的，并在病毒工厂中发挥重要作用，以制造新的病毒副本。所有这些都将使我们更好地了解病毒如何利用这些宿主蛋白质在细胞中繁殖。这将帮助我们更好地理解鼻病毒，这种数千年来与人类一起进化的病毒，是如何以非常有效的方式利用我们的细胞进行繁殖的，这是我们每个人每年都会发生的事情。反过来，这些知识将有助于设计新的分子来阻止这种情况，从而防止病毒繁殖。

Rhinoviruses are responsible for most common colds, causing billions of infections in humans every year across the globe. Although rhinovirus infections are associated with huge health, economic and social costs, there is no approved antiviral or vaccine against rhinoviruses. So far, around 170 different varieties of rhinoviruses have been identified and all efforts to make an effective vaccine have failed to date. Attempts to make antiviral drugs that directly target the virus have not been effective neither, partly because rhinoviruses are able to mutate very easily, and quickly develop resistance.As rhinoviruses need to enter and interact with host cells to multiply, a new strategy for making an antiviral drug may be to target the interactions between the virus and the host cells, rather than the virus itself. For this kind of antiviral strategy, we first need to understand how the virus interacts with host cells and uses them to reproduce. This area of research is still not very well understood for rhinoviruses, but also many related pathogenic viruses like poliovirus. Therefore, any discovery in this area promises to also help our understanding of other related viruses, which often use similar mechanisms to interact with host cells to reproduce.This project will investigate aspects of the interactions of rhinoviruses with host cells that have never been studied. This exciting project builds on a previous project funded by the Medical Research Foundation and Asthma UK.To reproduce in host cells, rhinoviruses build inside the cells that they infect some virus factories where new viruses are produced. These virus factories contain some viral proteins and some human proteins that are hijacked by the viral proteins to help them produce new viruses. While we know which are the viral proteins involved, we still do not know all the human proteins that are hijacked and enable the virus to reproduce. During our previous project, we have identified some host proteins that are in physical contact with the viral proteins. In particular, 2 of them seem to be absolutely necessary for the virus to reproduce. By removing them from the cells or blocking them with chemicals, the virus cannot reproduce anymore. This discovery is very exciting and could lead, in the long term, to new strategies to block the multiplication of the virus in host cells. But we first need to understand in great detail how these host proteins allow the virus to reproduce. This project will investigate that.We will examine, in the different steps that the virus uses to reproduce, exactly which one(s) need the host protein that we identified. We will precisely analyse which of the viral proteins bind to the host proteins that we identified and how these interactions happen and play an important role in the virus factories, to make new copies of the virus.All this will give us a good understanding of how the virus uses these host proteins to reproduce in cells. This will help us to better understand how rhinoviruses, which have evolved with humans since thousands of years, use our cells in very efficient ways to reproduce, something that happens in each of us every year. In turn, this knowledge will help to design new molecules that could block this and therefore prevent the virus to reproduce.