Mosquito-borne viruses; targeting the bite.

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。随着气候变暖和全球化帮助蚊子传播，这些病毒，如那些导致寨卡病毒和登革热的病毒，正在感染更多的人，并传播到新的国家。确定患者对这一大群异质病原体的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。蚊媒病毒在蚊子叮咬将病毒吐入皮肤时传播给人。这是感染的关键阶段，所有此类感染都是如此。我们最近发现，与病毒共同注射的蚊子唾液中的蚊子衍生因子对感染有非常显著的促进作用。令人兴奋的是，我们已经确定了一种唾液因子，唾液激肽(SK)，它是部分负责的。SK的工作原理是诱导血液内皮屏障功能障碍，使白细胞超级涌入咬合处，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。)确定蚊子唾液中的因子，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。)确定对小鼠接种针对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--我们将使用多种方法的组合来解决1)。确定唾液诱导原代培养的血内皮细胞屏障功能障碍的参数(屏障功能分析和转录组分析)。基于siRNA对蚊子唾液基因进行有针对性的筛选，以确定已确定的唾液基因在调节内皮屏障功能中的作用(在体外、体内和培养的人类皮肤外植体中)。用免疫球蛋白诱导疫苗在体内靶向蚊子唾液成分这个跨学科项目将独特地结合免疫学、媒介生物学、病毒学和血管生物学。它有可能让我们了解病毒在节肢动物/哺乳动物界面上的传播，以及针对蚊子唾液的新型疫苗的开发，以减少疾病负担。抗唾液疫苗的使用可能具有广泛的适用性，因为这些病毒通过唾液感染的增强被广泛观察到。

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.