Novel mechanisms of necroptosis subversion by human cytomegalovirus

人类巨细胞病毒（HCMV）感染世界上大多数人，并建立一个持续的，终身感染。虽然感染者通常不会生病，但对于免疫功能低下的患者，如移植受者，这种疾病可能是毁灭性的，他们会遭受器官排斥、多器官衰竭甚至死亡。此外，未出生的婴儿感染丙型巨细胞病毒的风险特别大，无论是在怀孕期间感染丙型巨细胞病毒的母亲还是已经感染丙型巨细胞病毒的母亲。总体而言，约有1/100的妊娠受到影响，HCMV是导致儿童耳聋和智力残疾的主要感染原因，也是导致出生缺陷的最重要病毒原因之一。抵御HCMV和其他病毒的第一道防线之一是“细胞死亡途径”，即受感染的细胞死亡以防止病毒传播。为了抵消这种防御，并促进它们的成功复制，包括HCMV在内的一些病毒抑制了这些细胞途径。我们的目标是了解HCMV如何防止细胞死亡。我们已经有了重要的发现，一种叫做UL36的病毒蛋白抑制了一种关键的细胞死亡途径，叫做坏死性凋亡。此外，我们的初步数据表明存在其他尚未发现的抑制细胞死亡的HCMV抑制剂。至关重要的是，详细了解UL36和其他HCMV坏死性坏死抑制剂的功能将使我们能够开发新的抗病毒治疗方法，恢复坏死性坏死，作为抵抗感染的重要防御。我们将(1)确定和描述HCMV抑制坏死下垂的新途径(2)确定HCMV如何靶向坏死下垂途径成分进行破坏；(3)从结构上了解每种病毒性坏死性坏死抑制剂如何与其细胞蛋白靶点相互作用。为了实现这些目标，我们将研究皮肤细胞和免疫传感细胞，它们在HCMV感染中都发挥着重要而独特的作用。了解HCMV和其他病毒如何破坏坏死坏死途径将最终使我们能够开发重要的新疗法来预防由HCMV引起的疾病。至关重要的是，这些知识还将提高我们对细胞死亡的理解，这将有利于包括败血症、神经退行性疾病和癌症在内的多个研究领域。

Human cytomegalovirus (HCMV) infects most people worldwide, and establishes a persistent, lifelong infection. Although infected individuals are not usually ill, in immunocompromised patients such as transplant recipients the disease can be devastating, suffering organ rejection, multi-organ failure and even death. Furthermore, unborn babies are at particular risk from HCMV, both in mothers infected during pregnancy and mothers who already have the virus. Overall ~1/100 pregnancies are affected, and HCMV is the leading infectious cause of deafness and intellectual disability in children, and one of the most significant viral causes of birth defects.One of the first lines of defence against HCMV and other viruses are 'cell death pathways', by which infected cells die to prevent viral spread. To counteract this defence, and promote their successful replication, some viruses including HCMV inhibit these cellular pathways.We aim to understand how HCMV prevents cell death. We have made the crucial discovery that a viral protein called UL36 inhibits a key cell death pathway called necroptosis. Furthermore, our initial data suggests the existence of other, as yet undiscovered HCMV inhibitors of cell death. Critically, a detailed understanding of how UL36 and other HCMV necroptosis inhibitors function will enable us to develop new antiviral treatments that restore necroptosis as a vital defence against infection.We will (1) identify and characterise new ways HCMV inhibits necroptosis (2) determine how HCMV targets necroptosis pathway components for destruction; (3) gain a structural understanding of how each viral necroptosis inhibitor interacts with its cellular protein target. To achieve these aims, we will study skin cells and immune sensing cells, which both play vital yet distinct roles in HCMV infection.Understanding how HCMV and other viruses subvert necroptosis pathways will eventually allow us to develop vital new treatments to prevent diseases caused by HCMV. Crucially, this knowledge will also improve our understanding of cell death, which will benefit multiple lines of research including into sepsis, neurodegenerative disease and cancer.