From cells over organisms to populations - Characterization of outcomes of emerging alphavirus infections

甲病毒在人类中引起严重的急性和慢性疾病，包括流行病学上最相关的甲病毒基孔肯雅病毒（CHIKV）的长期衰弱性关节痛，该病毒现已传播到四大洲，影响数百万人。在拉丁美洲，CHIKV遇到了两种广泛分布的、可能正在扩增的、抗原相关的本土甲病毒，即Mayaro（MAYV）和Una病毒（UNAV）。由于最近CHIKV的引入，拉丁美洲是一个独特的环境，以了解在适应不同的脊椎动物和无脊椎动物宿主使基因组和血清学分析复杂化之前，甲病毒传播和发病机制的基本特性。最近，基质重塑相关蛋白8（MXRA 8）和四个半LIM结构域蛋白1（FHL 1）已成为甲病毒进入和RNA复制的关键辅因子，增强了我们对甲病毒-宿主相互作用的理解。然而，甲病毒免疫相互作用知之甚少，挑战即将到来的甲病毒疫苗接种计划。COALITION项目加入了2个德国和2个法国的PI，这些PI具有独特的优势，通过对甲病毒诊断，动物模型，细胞免疫，宿主因素和获得相关生物材料的独特初步工作来研究甲病毒免疫。COALITION将在单个项目中以前所未有的广度调查甲病毒免疫相互作用和流行病学，在单个细胞、整个生物体和群体的水平上。在细胞水平上，COALITION将在体外和离体破译单特异性和双重甲病毒感染的特征，分析细胞状态和细胞内在先天免疫反应，深化CHIKV，MAYV和UNAV感染的宿主因素的鉴定，并研究同型和异型抗体对感染的影响。在整个生物体水平上，COALITION将通过详尽分析其甲病毒免疫背景和食蟹猴感染模型来评估急性感染CHIKV和适当对照患者的免疫增强，该模型允许对CHIKV、MAYV和UNAV之间的异型免疫增强和交叉保护、组织病毒传播/多样性的程度进行受控评估。在人群水平上，可能防止CHIKV出现的社区保护性免疫将通过全大陆差异血清流行率研究、地理空间建模和地理空间重建进行评估。通过独特的强大血清学数据验证的机器学习算法将用于预测MAYV和CHIKV在拉丁美洲的未来传播。COALITION的结果将深刻提高对甲病毒发病机制的理解，并传播和立即影响针对这些新出现的人类健康威胁的疫苗计划，有助于避免疫苗安全性的意外缺乏，例如最近观察到的登革热疫苗。

Alphaviruses cause severe acute and chronic disease in humans, including long-term debilitating arthralgia in the case of the epidemiologically most relevant alphavirus Chikungunya virus (CHIKV) that has by now spread across four continents, affecting millions of individuals. In Latin America, CHIKV meets two broadly distributed, likely expanding, antigenically related autochthonous alphaviruses, namely Mayaro (MAYV) and Una virus (UNAV). Because of the recent CHIKV introduction, Latin America is a unique setting to understand the fundamental properties underlying alphaviral spread and pathogenesis before adaptation to different vertebrate and invertebrate hosts complicates genomic and serologic analyses. Recently, matrix-remodeling-associated protein 8 (MXRA8) and four-and-a-half LIM domain protein 1 (FHL1) have emerged as key co-factors of alphavirus entry and RNA replication, enhancing our understanding of alphavirus-host interactions. However, the alphaviral immune interplay is poorly understood, challenging imminent alphavirus vaccination programmes. The COALITION project joins 2 German and 2 French PIs that are uniquely positioned to investigate alphavirus immunity by unique preliminary work into alphavirus diagnostics, animal models, cellular immunity, host factors, and access to relevant biological materials. COALITION will investigate alphavirus immune interplay and epidemiology at unprecedented breadth in a single project, on the level of individual cells, of whole organisms and of populations. On the level of cells, COALITION will decipher in vitro and ex vivo the characteristics of monospecific and dual alphaviral infections, analyze the cellular state and cell-intrinsic innate immune responses, deepen the identification of host factors of CHIKV, MAYV and UNAV infection and study the impact of homotypic and heterotypic antibodies on infection. On the level of whole organisms, COALITION will assess immune enhancement in patients acutely infected with CHIKV and adequate controls by exhaustively analyzing their alphaviral immune background and within cynomolgus macaque infection models that allow controlled assessments of the extent of heterotypic immune enhancement and cross-protection, tissue virus spread/diversity between CHIKV, MAYV and UNAV. On the population level, community protective immunity potentially preventing CHIKV emergence will be assessed by continent-wide differential seroprevalence studies, geospatial modelling and phylogeographic reconstructions. Machine learning algorithms validated by uniquely robust serological data will be used to project the future spread of MAYV and CHIKV across Latin America. The results of COALITION will profoundly enhance the understanding of alphaviral pathogenesis and spread and immediately impact vaccine programmes against these emerging threats for human health, contributing to avoid unexpected lack of vaccine safety such as recently observed with a dengue vaccine.