Antiviral restriction factors: Understanding determinants of host range and barriers to species-jumping in livestock viral disease

最近，一种可能源自蝙蝠的冠状病毒在人畜共患病中的传播突显了宿主物种通过病毒跳跃的重要性，导致了新冠肺炎的人类大流行。然而，病毒从动物跳到人类身上是一个相对不常见的事件。大多数病毒实际上被隔离在它们的正常宿主物种中，不能感染其他物种。这是因为病毒通常已经调整得很好，只感染一个或有限数量的特定物种。病毒正常宿主范围之外的物种呈现不同的宿主环境，其中包含可以防止病毒感染的陌生障碍或屏障。目前，我们对防止宿主物种跳跃的这些屏障，包括那些保护人类免受大多数动物病毒感染的屏障，了解得很少。在这个项目中，我们的目标是确定阻止动物病毒跳跃物种的障碍，包括感染人类。更好地了解这些障碍是什么，可以增强我们预测哪些病毒可能从动物传播到人类的能力。提高这一预测能力有助于减少或预防病毒性人畜共患病的破坏性影响。我们将重点关注牲畜的病毒，因为尽管人畜共患病源于野生动物的高调，但实际上99%的人畜共患病是由接触牲畜引起的，剩下的1%是由于接触野生动物贸易引起的。一个既定的障碍是病毒无法进入其自然宿主范围之外的物种的细胞。病毒通过细胞表面的受体分子进入细胞，病毒可以高度专门化地使用特定的受体。不同物种之间受体分子的差异，可以阻止病毒进入不同物种的细胞。然而，细胞进入并不总是感染的屏障。例如，口蹄疫病毒(FMDV)会导致猪和牛患病，但不能感染人类，但它进入人类细胞的效率与牛细胞一样高。牛呼吸道合胞病毒(BRSV)和猪水泡病病毒(SVDV)也有类似的观察结果。这意味着必须有其他屏障来保护人类免受这些家畜病毒的感染。我们怀疑这些其他障碍是人类先天免疫系统的一部分，特别是干扰素刺激基因(ISGs)。ISG在病毒感染期间被激活，有数百种不同的ISG，每个ISG都有专门的抗病毒功能，每个ISG都像是“瑞士军队抗病毒刀”上的一个不同的“工具”。虽然大多数工具在不同的哺乳动物物种之间是相同的，但每个物种都有一些独特的工具。例如，人类拥有家畜所没有的某些“瑞士军刀工具”。这些独特的基因可能专门用来保护人类免受特定病毒的感染。我们筛选了一个包含500多个不同的人类ISG的文库来检测抗口蹄疫病毒的活性，并发现了牛或猪中不存在的基因或“限制因子”。这些基因可能会保护人类和其他一些哺乳动物免受口蹄疫病毒的感染。我们想更详细地确定哺乳动物“瑞士军队抗病毒刀”中的这些基因如何防止物种跳跃，包括进入人类、口蹄疫病毒和其他牲畜病毒。

The importance of host species jumping by viruses has been recently highlighted by the zoonotic spread of a coronavirus likely originating in bats, resulting in the human pandemic of COVID-19. However, viruses jumping from animals to humans is a relatively uncommon event. Most viruses are effectively marooned in their normal host species and are unable to infect other species. This is because viruses have usually become finely tuned to infect just one or a limited number of specific species. Species outside the viruses normal host range present a different host environment containing unfamiliar obstacles or barriers that can prevent virus infections. At present we have a poor understanding of most of these barriers that prevent host species jumping including those that protect humans from infections with most animal viruses. In this project we aim to identify the barriers that prevent animal viruses from jumping species, including infecting humans. A better understanding of what these barriers are could enhance our ability to predict what viruses are likely to jump from animals to humans. Improving this prediction capability could help reduce or prevent the devastating impacts of viral zoonoses. We will focus on viruses of livestock animals, because despite the high profile of zoonoses originating from wildlife, in fact 99% of zoonotic infections are caused by contact with livestock and only the remaining 1% is due to contact with wildlife trade. One established barrier is the inability of a virus to enter the cell of a species outside its natural host range. Viruses enter cells using molecules on the cell surface known as receptors and viruses can be highly specialised to use a specific receptor. Variation in receptor molecules between different species, can prevent a virus from being able to enter cells of a different species. However, cell entry is not always a barrier to infection. For example, foot-and-mouth disease virus (FMDV) causes disease in pigs and cows, but is unable to infect humans, yet it enters human cells just as effectively as bovine cells. Similar observations have been made for bovine respiratory syncytial virus (bRSV) and swine vesicular disease virus (SVDV). This means there must be other barriers that protect humans from infections with these livestock viruses. We suspect these other barriers are part of the human innate immune system, specifically interferon stimulated genes (ISGs). ISGs are activated during viral infections, there are hundreds of different ISGs, each with a specialised antiviral function, each one acting like a different "tool" on a "Swiss army antiviral knife". While the bulk of the tools are the same between different mammalian species, each species has a few tools that are unique to it. For example, humans have certain "Swiss army knife tools" that are absent in livestock animals. These unique genes may be specialised to protect humans from infections against specific viruses. We screened a library containing over 500 different human ISGs for anti-FMDV activity and have identified genes or 'restriction factors' that are not present in cows or pigs. These genes likely protect humans and some other mammals from FMDV infections. We would like to determine in greater detail how these genes in the mammalian "Swiss army antiviral knife" protects against species jumping including into humans, by FMDV and other livestock viruses.