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

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

Herpesviruses form an ancient and widespread family of DNA viruses that have coevolved with humans for millions of years. Nine different herpesviruses infect humans and establish lifelong infections that persist silently in the body, allowing them to evade elimination by the immune system. Nevertheless, frequent reactivations enable viruses to spread within the body and between individuals. Well-known members of this family include herpes simplex viruses, varicella zoster virus, human cytomegalovirus, and Epstein–Barr virus. Human herpesviruses are extremely common: depending on the virus, between 20% and 90% of the global adult population is infected. As a result, most people carry several herpesviruses throughout their lifetime. While infections are often mild or asymptomatic, a significant health burden arises from severe complications in vulnerable individuals. These include eye infections that can lead to blindness, life-threatening brain inflammation, and increasing evidence links herpesvirus infections to age-related conditions such as dementia and cardiovascular disease. Given their high prevalence and the limited availability and effectiveness of current vaccines and antiviral treatments, herpesviruses continue to pose a substantial challenge to public health worldwide. A major obstacle to improving prevention, diagnosis, and treatment is our incomplete understanding of how human cells naturally defend themselves against viral infection. In particular, the interactions between viruses and host cell defence mechanisms remain poorly understood. Addressing this knowledge gap is essential for the development of innovative and more effective antiviral strategies. Therefore, this project aimed to identify the role of a natural cellular quality-control mechanism, known as nonsense-mediated RNA decay (NMD), in restricting herpesvirus infection. NMD normally protects cells by identifying and degrading faulty RNA molecules, thereby ensuring proper gene expression. However, its role in controlling viral infections has remained largely unexplored. Using herpes simplex virus type 1 (HSV-1) as a prototypical model system, the project investigated how this cellular pathway influences viral replication and infection outcome. The project demonstrated that NMD plays a previously unrecognised role in limiting herpesvirus infection. By showing that this host defence mechanism actively restricts viral replication across different experimental settings, the research achieved its central objective of clarifying how human cells counteract herpesvirus infection. These findings contribute to a deeper understanding of virus-host interactions that influence disease progression and, in the longer term, may support the identification of new targets for antiviral therapies. This is particularly relevant in the current European and global context, where emerging and re-emerging viruses with neurological involvement are expanding into densely populated regions due to environmental change, demographic shifts, and increased human-animal contact.

Data: CORDIS, © European Union