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

从细胞、生物体到群体——新发甲病毒感染结果的表征

• 批准号: 446048345
• 负责人: Professor Dr. Jan Felix Drexler, since 9/2023
• 金额: --
• 依托单位: Liverpool School of Tropical Medicine
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/446048345?language=en
• 关键词: cells; over; organisms; populations; Characterization

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.

甲型病毒在人类中造成严重的急性和慢性疾病，包括长期衰弱的关节痛，在流行病学上最相关的甲型病毒基孔肯雅病毒(CHIKV)的情况下，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、可能正在扩展的抗原性相关的本土甲型病毒，即Mayaro病毒(MAYV)和Una病毒(UNAV)。由于最近引入了CHIKV，拉丁美洲是一个独特的环境，可以在适应不同的脊椎动物和无脊椎动物宿主之前了解甲型病毒传播和致病的基本特征，这使基因组和血清学分析变得复杂。最近，基质重塑相关蛋白8(MXRA8)和四个半LIM结构域蛋白1(FHL1)已成为甲病毒进入和RNA复制的关键辅助因子，加深了我们对甲病毒与宿主相互作用的理解。然而，人们对甲型病毒免疫的相互作用知之甚少，对迫在眉睫的甲型病毒疫苗接种计划构成了挑战。该联盟项目加入了2个德国和2个法国PI，这两个PI通过在甲病毒诊断、动物模型、细胞免疫、宿主因素和相关生物材料的获取方面进行独特的初步工作，在研究甲型病毒免疫方面具有独特的地位。联盟将在一个单一的项目中，在单个细胞、整个生物体和种群的水平上，以前所未有的广度研究甲型病毒免疫相互作用和流行病学。在细胞水平上，联合将在体外和体外破译单特异性和双甲病毒感染的特征，分析细胞状态和细胞固有免疫反应，深化对CHIKV、MAYV和UNAV感染宿主因素的识别，并研究同型和异型抗体对感染的影响。在整个生物体的水平上，联合将通过详尽分析甲型病毒免疫背景和食蟹猴感染模型来评估急性感染CHIKV的患者和足够对照的免疫增强情况，这些模型允许受控地评估CHIKV、MAYV和UNAV之间的异型免疫增强和交叉保护的程度、组织病毒的传播/多样性。在人口层面上，将通过全大陆差异血清抗体研究、地理空间建模和系统地理重建来评估有可能防止CHIKV出现的社区保护性免疫。经过独特可靠的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。联盟的结果将深刻地加强对甲型病毒致病机理和传播的了解，并立即影响针对这些对人类健康的新威胁的疫苗计划，有助于避免像最近观察到的登革热疫苗那样意外地缺乏疫苗安全性。