Physiological Role of Nonsense-Mediated Decay in Herpes Simplex Virus Infection and Pathogenicity

ended

Virus infections cause a major healthcare burden worldwide. The neurotropic human herpes simplex virus 1 (HSV-1) establishes life-long latent infection in neurons, from which it frequently reactivates to disseminate within the population. Clinical complications caused by HSV-1 infections range from mild (herpes labialis) to sight- (keratitis) and even life-threatening diseases (encephalitis). Prevention and treatment of HSV-1 infections are considered a top priority by the WHO. However, development of vaccines and improved therapeutic approaches is hindered by our incomplete understanding of the virus-host interactions that govern infection and disease, especially the interplay between HSV-1 and intrinsic neuronal defenses. The highly conserved cellular RNA degradation pathway nonsense-mediated decay (NMD), which regulates expression of ~10% of cellular transcripts and controls numerous fundamental processes, has recently emerged as an important regulator of neuronal function. Based on my previous postdoctoral studies that revealed a major role for NMD in controlling infection by oncogenic human herpesviruses combined with my preliminary data on HSV-1, I hypothesize that NMD provides an intrinsic defense mechanism that controls HSV-1 infection. In this fellowship, I propose to combine my experience and the expertise of the host institute to determine the physiological relevance and molecular mechanism by which NMD controls HSV-1 infection in its natural human host. Successful completion of my project will lead to improved insight into the virus-host interactions that control infection of HSV-1, thereby providing novel therapeutic targets to combat HSV-1 infection and pathogenesis. Moreover, the extensive and multidisciplinary training in research and transferrable skills provided by this fellowship will be invaluable for my goal of becoming an all-round competitive scientist leading an independent research group focused on intrinsic immunity to neurotropic viruses.