Mechanisms of helminth induced antiviral immunity to RSV infection

蠕虫诱导RSV感染抗病毒免疫的机制

• 批准号: MR/L008394/1
• 负责人: Jürgen Schwarze
• 金额: $ 63.85万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL008394%2F1
• 关键词: Mechanisms; helminth; induced; antiviral; immunity

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.

在全世界的婴儿和幼儿中，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%的婴儿必须因RSV细支气管炎住院，其中一些婴儿会发展成非常严重的疾病，有时甚至危及生命。当感染后出现大量病毒颗粒时，尤其如此。RSV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。由于治疗成本和更广泛的社会成本（例如父母/护理人员的工作日损失），RSV造成了重大的经济负担。尽管如此，没有具体的治疗或有效的，广泛可用的预防性干预措施存在，迫切需要新的方法。帕利珠单抗是一种抗RSV的单克隆抗体，可以预防约50%的住院，但由于成本高，其使用仅限于富裕国家的一小群高危婴儿。我们最近发现，肠道寄生虫感染可以减少RSV感染小鼠模型中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。在蠕虫感染的小鼠中，我们还发现参与遏制和消除病毒的抗病毒基因的表达增加。这些观察结果表明，肠道蠕虫感染可导致肺中的抗病毒状态，这减少了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/或物质负责寄生虫感染期间的抗病毒作用，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。我们还将使用这个模型来测试是否蠕虫衍生的产品单独，而不是蠕虫感染的整个过程，足以达到所需的抗病毒效果。为了弄清楚肠道寄生虫感染是否也会导致人类对RSV的抗病毒作用，我们将研究乌干达的儿童，这些蠕虫感染仍然很常见。我们将从RSV最初生长的鼻内壁和血液样本中采集少量样本，以比较有和没有肠道蠕虫感染的儿童之间的抗病毒基因水平（在实验室中有和没有RSV暴露）。这些研究将让我们找出蠕虫感染期间产生的免疫细胞或物质，导致肺部的抗病毒状态，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。

项目成果

Enteric helminth-induced type I interferon signaling protects against pulmonary virus infection through interaction with the microbiota.

肠蠕虫诱导的I型干扰素信号传导通过与微生物群相互作用来预防肺病毒感染。

• DOI: 10.1016/j.jaci.2017.01.016
• 发表时间: 2017-10
• 期刊: The Journal of allergy and clinical immunology
• 作者: McFarlane AJ;McSorley HJ;Davidson DJ;Fitch PM;Errington C;Mackenzie KJ;Gollwitzer ES;Johnston CJC;MacDonald AS;Edwards MR;Harris NL;Marsland BJ;Maizels RM;Schwarze J
• 通讯作者: Schwarze J

Commensal-pathogen interactions in the intestinal tract: lactobacilli promote infection with, and are promoted by, helminth parasites.

• DOI: 10.4161/gmic.32155
• 发表时间: 2014-07-01
• 期刊: Gut microbes
• 影响因子: 12.2
• 作者: Reynolds LA;Smith KA;Filbey KJ;Harcus Y;Hewitson JP;Redpath SA;Valdez Y;Yebra MJ;Finlay BB;Maizels RM
• 通讯作者: Maizels RM

HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33.

• DOI: 10.1016/j.immuni.2017.09.015
• 发表时间: 2017-10-17
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Osbourn M;Soares DC;Vacca F;Cohen ES;Scott IC;Gregory WF;Smyth DJ;Toivakka M;Kemter AM;le Bihan T;Wear M;Hoving D;Filbey KJ;Hewitson JP;Henderson H;Gonzàlez-Cìscar A;Errington C;Vermeren S;Astier AL;Wallace WA;Schwarze J;Ivens AC;Maizels RM;McSorley HJ
• 通讯作者: McSorley HJ

Cathelicidins Have Direct Antiviral Activity against Respiratory Syncytial Virus In Vitro and Protective Function In Vivo in Mice and Humans.

• DOI: 10.4049/jimmunol.1502478
• 发表时间: 2016-03-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Currie SM;Gwyer Findlay E;McFarlane AJ;Fitch PM;Böttcher B;Colegrave N;Paras A;Jozwik A;Chiu C;Schwarze J;Davidson DJ
• 通讯作者: Davidson DJ