Three species viral zoonotic infections - a systems virology analysis

最近发生的引人注目的事件突出了蝙蝠病毒向人类的传播，通常涉及中间养殖/伴侣动物宿主。其中包括亨德拉病毒（蝙蝠-马-人）、尼帕病毒（蝙蝠-猪-人）、sars冠状病毒（蝙蝠-果子狸-人）和中东呼吸综合征冠状病毒（蝙蝠-骆驼-人）。因此，有一种新病毒从野生动物传播给养殖/伴侣动物和/或人类的既定模式。这种通过另一种动物从蝙蝠传染给人类的疾病——被称为人畜共患病——在未来很有可能继续发生。蝙蝠占所有现存哺乳动物的近20%，它们几乎遍布地球上的任何地方，这意味着从蝙蝠传播给动物和人类的新病毒可能发生在任何地方。蝙蝠分布广泛，携带一系列类似于MERS-CoV/SARS-CoV的病毒，在英国，蝙蝠与一系列野生和养殖动物接触。因此，与其他任何地方一样，这里也有可能爆发新的疫情。除了对人类健康的威胁外，这种三期人畜共患病还带来两个潜在的粮食安全问题；一是这种新型病毒直接影响动物健康（例如，影响范围从无法增重到死亡）。第二是由于对人类健康的威胁而对粮食安全造成的间接影响，例如尼帕病毒暴发导致了对养猪的大规模屠宰。了解疾病可能变得多么严重，或者在人畜共患事件中哪些动物可能受到影响的一个关键障碍是，我们对新出现的病毒如何与不同动物的转录和翻译系统的调节相互作用知之甚少。这意味着我们不了解病毒如何与新的宿主物种相互作用，这将影响病毒是否成功复制以及感染是否会导致疾病或死亡。在人类病毒研究中，高通量蛋白质组学/转录组学/相互作用组学等技术已经成功地用于揭示病毒如何调节和与数千种人类基因和蛋白质相互作用。这种新的“系统病毒学”方法甚至提出了对抗或控制这种疾病的方法。对可能影响粮食安全的人畜共患病毒进行同样细致的研究，可以帮助我们了解这些病毒在不同动物和媒介物种中致病性的显著差异。至关重要的是，这将揭示病毒是如何适应并传染给其他动物的，或者某些物种是否比其他物种更容易传染。反过来，这将有助于为政策提供信息，因为它可以预测哪些动物很容易成为新的宿主，或者哪些动物可能遭受严重的致病反应，从而可以相应地加以控制。在非人类物种（即动物宿主和人畜共患感染的中间宿主）中进行这类研究的能力存在许多严重的瓶颈。这是因为“系统病毒学”方法需要检测和鉴定基因转录物和蛋白质的高通量方法，这在非人类物种中仍然是一个主要挑战。即使有一个可用的基因组序列，它也不会被关于i)同源基因的鉴定，ii)基因转录本的完整补体，例如，差异剪接转录本，以及iii)这些转录本编码的蛋白质的注释。我们已经开发了一种世界领先的技术（称为PIT分析），使我们能够使用高通量技术来研究任何动物的病毒-宿主相互作用，其精度与我们目前应用于人类疾病的精度相同。在这个项目中，我们将研究一种人畜共患病毒如何与三种不同的动物（包括人类）相互作用，确定受影响的不同细胞途径，帮助我们了解病毒如何从一种动物跳到另一种动物，并提出未来对抗它们的方法。

Recent high profile events highlight the transmission of bat viruses to humans, usually involving an intermediate farmed/companion animal host. These include Hendra (bats - horses - humans), Nipah (bats - pigs - humans), SARS-CoV (bats - palm civet - humans) and MERS-CoV (bats - camels - humans). Thus, there is an established paradigm of new viruses passing from wild animals to farmed/companion animals and/or humans. There is every possibility that this kind of jump from bats to humans via another animal - which is known as a zoonosis - could keep happening in the future. Bats make up almost 20% of all living mammals and they are found almost everywhere on the planet, which means that new viruses spreading from bats to animals and humans could happen anywhere. Bats are widespread and carry a range of viruses similar to MERS-CoV/SARS-CoV and in the UK, bats come into contact with a range of wild and farmed animals. Thus, a new outbreak is as likely to happen here as anywhere else. In addition to the threat to human health, this kind of three-stage zoonosis poses two potential food security issues; one is that the novel virus impacts animal health directly (e.g. effects ranging from a failure to gain weight to mortality). The second is an indirect impact on food security resulting from the threat to human health, e.g. Nipah virus outbreaks have resulted in the wholesale slaughter of farmed pigs.A key barrier to understanding how serious a disease might become, or which animals might be affected in zoonotic events, is that we have little information on how the emerging virus interacts with the regulation of transcriptional and translational systems in different animals. This means we do not understand how the virus might interact with a new host species, which will influence whether the virus successfully replicates and whether the infection will cause disease or fatalities.In human virus research, techniques such as high-throughput proteomics/transcriptomics/interactomics have been successfully used to reveal how viruses modulate and interact with thousands of human genes and proteins. This new "systems virology" approach even suggests ways of combating or managing the disease. Studying a zoonotic virus with a potential to impact food security, in the same level of detail, could help us understand the pronounced differences in pathogenicity of these viruses in different animal and vector species. Crucially, this will reveal how viruses adapt and jump into other animals, or if certain species jumps are more likely than others. In turn, this will help inform policy by allowing predictions of which animals may readily act as new hosts, or are likely to suffer severe pathogenic responses, and thus can be controlled accordingly. The ability to do this type of research in non-human species (i.e. the animal reservoirs and intermediate hosts of zoonotic infections) has a number of serious bottlenecks. This is because the "systems virology" approach requires high-throughput methods of detecting and identifying gene transcripts and proteins, which is still a major challenge in non-human species. Even if there is a genome sequence available, it will not have been annotated with regard to i) the identification of orthologous genes, ii) the full complement of gene transcripts, for example, differentially spliced transcripts, and iii) the proteins encoded by these transcripts. We have developed a world-leading technique (called PIT analysis) that allows us to use high-throughput techniques to study virus-host interactions in any animal with the same precision as we can currently apply to human diseases. In this project we will examine how a zoonotic virus interacts with three different animals (including humans), identifying the different cellular pathways that are affected and help us understand how viruses jump from one animal to another and suggesting ways of combating them in the future.