Mechanisms of helminth induced antiviral immunity to RSV infection

在全世界的婴幼儿中，呼吸道合胞病毒（RSV）是一种称为细支气管炎的胸部感染的最常见原因，并导致严重的肺部炎症。在英国，2%的婴儿因呼吸道合胞病毒毛细支气管炎而住院，其中一些人发展成非常严重的疾病，有时甚至危及生命。这种情况尤其发生在感染后存在大量病毒颗粒的情况下。由呼吸道合胞病毒引起的死亡在英国很少见，但在发展中国家却是一个严重的问题。由于治疗费用和更广泛社会的费用（例如父母/照顾者的工作损失天数），呼吸道合流病毒造成了重大的经济负担。尽管如此，目前还没有具体的治疗方法或有效的、广泛可用的预防干预措施，迫切需要新的方法。帕利维珠单抗是一种抗RSV的单克隆抗体，可使住院率降低约50%，但由于成本高昂，它的使用仅限于富裕国家的一小群高风险婴儿。我们最近发现，在RSV感染的小鼠模型中，肠道寄生虫感染可以减少肺部病毒颗粒的数量，并阻止驱动炎症的免疫系统细胞的积累。在受蠕虫感染的小鼠中，我们还发现参与抑制和消除病毒的抗病毒基因表达增加。这些观察结果表明，肠道蠕虫感染可导致肺部抗病毒状态，从而减少RSV感染中的病毒颗粒数量、免疫细胞反应、炎症和疾病严重程度。在这里，我们将首先使用我们的小鼠模型来研究小鼠免疫系统的哪些细胞和/或物质在寄生虫感染期间负责抗病毒作用，以及这些细胞和/或物质是否可以代替蠕虫感染来降低RSV感染的严重程度。我们还将使用该模型来测试单独的蠕虫衍生产品，而不是蠕虫感染的整个过程，是否足以达到预期的抗病毒效果。为了找出肠道寄生虫感染是否也会导致人类对呼吸道合胞病毒的抗病毒作用，我们将研究乌干达的儿童，那里这些蠕虫感染仍然很常见。我们将从患有和未患有肠道蠕虫感染的儿童的鼻子内壁（RSV最初生长的地方）采集小样本和血液样本，以比较感染和未感染肠道蠕虫的儿童的抗病毒基因水平（在实验室中有和没有接触RSV）。这些研究将让我们发现在蠕虫感染期间出现的哪些免疫细胞或物质导致肺部抗病毒状态，以及这些物质或细胞是否将成为开发严重RSV细支气管炎预防性治疗的有希望的新靶点。

In babies and toddlers worldwide, respiratory syncytial virus (RSV) is the most common cause of a type of chest infections called bronchiolitis and causes a severe lung inflammation. 2% of all babies in the UK have to be admitted to hospital with RSV bronchiolitis and some of them develop very severe and sometimes life threatening disease. This happens particularly when very high numbers of virus particles are present after infection. Death due to RSV is rare in the UK, but it is a significant problem in developing countries. Due to treatment costs and costs for the wider society (e.g. days lost at work for parents/ carers) RSV is responsible for a major financial burden. Despite all of this, no specific treatment or effective, widely available preventative interventions exist and novel approaches are urgently required. Palivizumab, a monoclonal antibody to RSV can prevent hospital admissions by about 50%, but due to high cost its use is limited to small groups of high risk infants in affluent countries. We have recently found that infection with a gut parasite worm can reduce the number of viral particles in the lungs in a mouse model of RSV infection and block the accumulation of the immune system cells that drive inflammation. In worm-infected mice, we also found an increased expression of antiviral genes that are involved in containing and eliminating the virus. These observations suggest that a worm infection of the gut can lead to an antiviral state in the lung which reduces numbers of viral particles, immune cell responses, inflammation, and disease severity in RSV infection. Here, we will initially use our mouse model to study which cells and/or substances of the mouse's immune system are responsible for the antiviral effects during parasite worm infection and whether these cells and/or substances can be used instead of worm infection to reduce the severity of RSV infection. We will also use this model to test whether worm-derived products alone, rather than the full process of worm infection, are sufficient for the desired antiviral effects. To find out if gut parasite worm infections also lead to antiviral effects against RSV in humans we will study children in Uganda where these worm infections are still common. We will take small samples from the inner lining of the nose, where RSV initially grows, and blood samples to compare the levels of antiviral genes (with and without RSV exposure in the laboratory) between children with and without gut worm infection. These studies will let us find out which immune cells or substances that arise during worm infection, lead to an antiviral state in the lung and whether these substances or cells will be promising new targets to develop preventive treatment for severe RSV bronchiolitis.