Mosquito-borne viruses; targeting the bite.

蚊媒病毒；

• 批准号: 2739762
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2739762
• 关键词: Mosquito; borne; viruses; targeting; bite.

The climate crisis is making mosquito-borne virus infections an increasing threat to human health. These viruses, such as those that cause Zika and dengue, are infecting more people and spreading to new countries as the climate warms and globalisation helps mosquitoes spread. Defining common determinants of patient susceptibility to this large group of heterogenous pathogens are key for informing the rational design of new pan-viral medicines.Mosquito-borne viruses are transmitted to people when biting mosquitoes spit virus into the skin. This is a key stage of infection that is common to all such infections. We have recently shown that mosquito-derived factors in mosquito saliva, co-injected with virus, have a highly significant enhancing effect on infection. Excitingly, we have already identified one salivary factor, sialokinin (SK), that is part-responsible. SK works by inducing blood endothelial barrier dysfunction, which enables a super-influx of leukocytes into the bite, which consequently become infected and replicate virus. ObjectivesThis project will transform our understanding of this key stage of mosquito-borne virus infection with the aim of identifying a novel pan-viral therapeutic strategy by,1.) defining how factors in mosquito saliva, including sialokinin, modulate blood endothelial barrier function, and so modulate host susceptibility to virus 2.) defining whether vaccination of mice against factors in mosquito saliva can interfere with its ability to enhance virus infectionExperimental approach - we will utilise a combination of approaches to1.) define the parameters by which saliva induces barrier dysfunction in primary cultures of blood endothelia (barrier function assays and transcriptome analysis)2.) undertake a targeted siRNA-based screen of mosquito salivary genes to define the role of identified salivary genes in modulating endothelial barrier function (in vitro, in vivo and in cultured human skin explants)3.) target mosquito salivary components with IgG-inducing vaccines in vivoThis interdisciplinary project will uniquely combine immunology, vector biology, virology and vascular biology. It has potential to inform our understanding of virus transmission at the arthropod/mammalian interface and the development of novel vaccines that target mosquito saliva to reduce disease burden. The use of anti-saliva vaccines may have wide applicability, as enhancement of infection by saliva is widely observed for these viruses.

气候危机使蚊媒病毒感染对人类健康构成越来越大的威胁。这些病毒，如引起寨卡和登革热的病毒，正在感染更多的人，并随着气候变暖和全球化帮助蚊子传播而传播到新的国家。确定患者对这一大群异质性病原体易感性的共同决定因素是合理设计新的泛病毒药物的关键。蚊子传播的病毒通过叮咬蚊子将病毒吐入皮肤传播给人类。这是感染的关键阶段，是所有此类感染的共同点。我们最近发现，蚊子唾液中的蚊子衍生因子与病毒共同注射，对感染具有非常显著的增强作用。令人兴奋的是，我们已经确定了一个唾液因子，唾液激肽（SK），这是部分负责。SK通过诱导血液内皮屏障功能障碍来发挥作用，这使得白细胞超流入叮咬，从而感染并复制病毒。本项目将改变我们对蚊媒病毒感染这一关键阶段的理解，目的是通过以下方式确定一种新的泛病毒治疗策略：定义蚊子唾液中的因子，包括唾液激肽，如何调节血液内皮屏障功能，从而调节宿主对病毒2的易感性。确定对小鼠接种抗蚊子唾液中因子的疫苗是否会干扰其增强病毒感染的能力实验方法-我们将利用多种方法的组合1.）定义唾液诱导血内皮原代培养物中屏障功能障碍的参数（屏障功能测定和转录组分析）2.）进行蚊子唾液基因的靶向siRNA筛选，以确定鉴定的唾液基因在调节内皮屏障功能中的作用（体外、体内和培养的人皮肤外植体）3.）以蚊子唾液成分为靶点IgG诱导疫苗的体内研究这个跨学科的项目将独特地联合收割机免疫学、载体生物学、病毒学和血管生物学。它有可能为我们了解节肢动物/哺乳动物界面的病毒传播和开发针对蚊子唾液的新型疫苗以减少疾病负担提供信息。抗唾液疫苗的使用可能具有广泛的适用性，因为对于这些病毒广泛观察到唾液的感染增强。