Coordination Funds

人类巨细胞病毒(HCMV)持续感染着世界上大多数人口。它的临床相关性和社会经济影响很大，但通常被低估。虽然健康人的巨细胞病毒感染通常是亚临床的，但在免疫功能低下的人中，危及生命的巨细胞病毒病是常见的。特别是，造血干细胞或实体器官移植的接受者会患上巨细胞病毒引起的肺炎、结肠炎、视网膜炎或移植物排斥反应，继而发生移植失败。更大的社会负担源于先天性巨细胞病毒感染，这是由于感觉神经性听力损失等终身健康损害造成的。此外，HCMV的持久性与老年人的心血管疾病和免疫衰老有关，这表明潜伏性的HCMV疾病影响到普通人群的很大一部分。抗人巨细胞病毒药物在临床应用中，由于其严重的不良反应和耐药性的产生，其疗效受到限制。最后，最近的临床前研究为预防和治疗基于巨细胞病毒的减毒活疫苗提供了有希望的数据，以对抗其他感染源(艾滋病毒、疟疾、结核病)和癌症。虽然目前还没有针对巨细胞病毒的疫苗，但基于巨细胞病毒的疫苗平台的研究正在进行。巨细胞病毒能够通过多种层级有序的机制操纵宿主免疫系统，特别是CD8T细胞和NK细胞。此外，巨细胞病毒通过扩大独特的免疫细胞亚群来重新编程CD8和NK细胞，而这些细胞亚群的功能特征却鲜为人知。通过新的高通量技术发现了数百种新的和非传统的CMV基因产物，这表明病毒的免疫调节可能比之前认为的要复杂得多。同时，各自的病毒蛋白也可能是CD8+T细胞迄今未被认可的多肽抗原的一大来源。这个RU的主要目标是弥合关于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主要知识空白。特别是，RU旨在了解CMV感染细胞的分子相互作用(包括。抗原提呈细胞(APC)与T细胞和NK细胞在分子、细胞和生物水平上。综合各种实验系统的发现，我们将能够将稳步增长的数据整合到全面的大纲中，从而能够绘制出CMV发病机制、逃避策略和免疫的大图。临床小组的整合将使RU的主要发现立即对维尔茨堡和弗莱堡大学医院以及汉诺威医学院(MHH)执行的诊断程序、风险分层和免疫疗法产生影响。RU将从维尔茨堡协调。

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.