Novel mechanisms of necroptosis subversion by human cytomegalovirus

点击翻译按钮获取中文摘要

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.