Coordination Funds

协调基金

• 批准号: 421450861
• 负责人: Professor Dr. Lars Dölken
• 金额: --
• 依托单位: Institut für Virologie und Immunbiologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/421450861?language=en
• 关键词: Coordination; Funds

The human cytomegalovirus (HCMV) persistently infects the majority of the world’s population. Its clinical relevance and socioeconomic impact is large, but commonly underappreciated. While HCMV infection of healthy individuals is usually subclinical, life-threatening HCMV disease is frequent among the immunocompromised. In particular, hematopoietic stem cell or solid organ transplant recipients suffer from HCMV-induced pneumonia, colitis, retinitis or graft rejection followed by transplant failure. An even larger social burden stems from congenital HCMV infection due to lifelong health impairments like sensorineural hearing loss. Moreover, HCMV persistence is associated with cardiovascular disease in the elderly and immunosenescence, indicating that insidious HCMV disorders affect a large swath of the general population. While antiviral drugs against HCMV are in clinical use, their benefit is limited by serious adverse effects and the development of drug-resistance. Finally, recent pre-clinical studies provided promising data for both prophylactic and therapeutic CMV-based live attenuated vaccines against other infectious agents (HIV, malaria, tuberculosis) and cancer. While a vaccine against HCMV is still not available, substantial efforts are thus being undertaken to generate and explore an HCMV-based vaccine platform.CMVs are notorious for their ability to manipulate large parts the host immune system, in particular CD8 T cells as well as NK cells, by multiple hierarchically ordered mechanisms. Moreover, HCMV reprograms CD8 and NK cells by inflating unique immune cell subpopulation with poorly understood functional features. The discovery of hundreds of new and non-conventional CMV gene products by novel high-throughput technologies indicates that viral immune modulation may be substantially more sophisticated than previously thought. At the same time, the respective viral proteins may also represent a large source of hitherto unappreciated peptide antigens for CD8+ T cells. An overarching objective of this RU is to close major gaps of knowledge about the immunological function of CMV gene products and their role in host immune system-pathogen interaction. In particular, the RU aims to understand the molecular interactions of CMV-infected cells (incl. antigen-presenting cells (APCs)) with T and NK cells at molecular, cellular and organism level. Bringing together findings from various experimental systems, we will be able to integrate the steadily growing number of data into comprehensive synopses, allowing to map big pictures of CMV pathogenesis, evasion strategies and immunity. The integration of clinical groups will enable key findings of the RU to immediately impact on the diagnostic procedures, risk stratification and immunotherapies executed at the University Hospitals Würzburg and Freiburg as well as Hannover Medical School (MHH).The RU will be coordinated from Würzburg.

人巨细胞病毒（HCMV）持续感染世界上大多数人口。其临床相关性和社会经济影响很大，但通常被低估。虽然健康个体的HCMV感染通常是亚临床的，但危及生命的HCMV疾病在免疫功能低下者中常见。特别地，造血干细胞或实体器官移植接受者患有HCMV诱导的肺炎、结肠炎、视网膜炎或移植物排斥，随后是移植失败。一个更大的社会负担来自先天性HCMV感染，由于终身健康损害，如感音神经性听力损失。此外，HCMV的持续存在与老年人的心血管疾病和免疫衰老有关，表明潜伏的HCMV疾病影响了大部分普通人群。虽然抗HCMV的抗病毒药物已在临床使用，但其益处受到严重不良反应和耐药性发展的限制。最后，最近的临床前研究为预防性和治疗性CMV减毒活疫苗提供了有希望的数据，这些疫苗针对其他传染性病原体（艾滋病毒、疟疾、结核病）和癌症。虽然针对HCMV的疫苗仍然不可用，但因此正在进行大量努力以产生和探索基于HCMV的疫苗平台XMV因其通过多个分级有序机制操纵宿主免疫系统的大部分，特别是CD 8 T细胞以及NK细胞的能力而臭名昭著。此外，HCMV通过使具有知之甚少的功能特征的独特免疫细胞亚群膨胀来重编程CD 8和NK细胞。通过新的高通量技术发现了数百种新的和非常规的CMV基因产物，这表明病毒免疫调节可能比以前认为的要复杂得多。同时，相应的病毒蛋白也可能代表迄今未被认识到的CD 8 + T细胞的肽抗原的大来源。该RU的总体目标是填补关于CMV基因产物的免疫功能及其在宿主免疫系统-病原体相互作用中的作用的知识的主要空白。特别是，RU旨在了解CMV感染细胞的分子相互作用（包括抗原呈递细胞（APC））与T细胞和NK细胞在分子、细胞和生物体水平上的相互作用。汇集来自各种实验系统的研究结果，我们将能够将稳步增长的数据整合到全面的概要中，从而绘制CMV发病机制，逃避策略和免疫力的大图。临床小组的整合将使RU的关键发现能够立即影响维尔茨堡和弗赖堡大学医院以及汉诺威医学院（MHH）执行的诊断程序、风险分层和免疫治疗。RU将从维尔茨堡协调。