Modulation of apoptosis by cytomegalovirus: analysis of new mechanisms to interfere with cytomegalovirus-induced disease

细胞凋亡，或程序性细胞死亡，是复杂生物系统发育和动态平衡控制中的一个重要过程。除了这些主要的管家作用外，细胞凋亡还提供了一种强大的防御机制，以抵御入侵的病原体，如病毒，因为它允许早期从宿主中清除受感染的细胞。疱疹病毒的一个基本属性是它们能够建立持续感染，并在宿主的一生中与其保持联系。这有力地强调了他们成功地与免疫系统的抗凋亡机制达成了协调。该项目的中心假设是，疱疹病毒，如小鼠和人类巨细胞病毒，编码的蛋白质干扰细胞死亡途径，从而绕过宿主防御，使病毒复制和传播得以进行。因此，我们的目标是识别和表征调节细胞凋亡的巨细胞病毒蛋白。这些研究将提高我们对病毒感染，特别是由巨细胞病毒引起的细胞凋亡控制的理解。人巨细胞病毒(HCMV)是一种能够在免疫系统不成熟或受损的个体中引起显著发病率和死亡率的病原体，如新生儿、艾滋病患者、移植受者和接受化疗药物治疗的人。因此，拟议的研究将有助于阐明可能与人类巨细胞病毒致病相关的分子机制，并将为合理设计合适的抗病毒药物和疫苗提供见解。了解宿主免疫逃避的病毒机制继续提高我们对复杂细胞途径的理解。因此，鉴于细胞凋亡的异常调节与退行性疾病、癌症和自身免疫性疾病的发生有关，所提出的研究将为开发针对这些病理疾病的新疗法提供有价值的见解。

Apoptosis, or programmed cell death is an essential process in developmental and homeostatic control of complex biological systems. In addition to these primary house keeping roles, apoptosis provides a powerful defence mechanism against invading pathogens, such as viruses, since it allows early elimination of infected cells from the host. A basic property of herpesviruses is their ability to establish persistent infection and remain in association with the host for its lifetime. This strongly underlines their success at reaching an accommodation with the immune system's anti-apoptotic mechanisms. The central hypothesis of this project is that herpesviruses, such as murine and human cytomegalovirus, encode proteins that interfere with cell death pathways thereby circumventing host defence so that viral replication and dissemination can proceed. Thus, the aims are to identify and characterise cytomegalovirus proteins that modulate apoptosis. These studies will improve our understanding of the control of apoptosis during viral infection, especially as caused by cytomegaloviruses. Human cytomegalovirus (HCMV) is a pathogen able to cause significant morbidity and mortality in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. Hence, the proposed studies will allow the elucidation of molecular mechanisms that may be relevant to the pathogenesis of HCMV in man and will provide insights into the rational design of suitable antiviral drugs and vaccines. Understanding viral mechanisms of host immune evasion continues to improve our understanding of complex cellular pathways. Therefore, given that abnormal regulation of apoptosis is implicated in the development of degenerative conditions, cancer and autoimmune disease, the proposed studies will provide valuable insight towards the development of new therapies for these pathological conditions.