Acute respiratory tract infections are a major cause of severe lower respiratory tract infections, resulting in significant morbidity and mortality, particularly in paediatric, elderly and immunocompromised populations. Despite this, prophylactic and therapeutic treatment options are limited. While viral specific inhibitors are being actively researched, they are often not broad spectrum and can lead to antiviral resistance. Host targeted therapies are a promising alternative, as they have the potential to be highly effective against a broad range of viruses.
This project aimed to investigate whether members of the Tripartite Motif (TRIM) family of proteins, which are intracellular E3 ubiquitin ligases, might represent targets for the development of antiviral host targeted therapies. To this end, a selection of 11 different human TRIM proteins (from a family of ~80) were experimentally over-expressed in human epithelial cells to test their potential as antiviral factors. Cells were then infected with either: respiratory syncytial virus (RSV), human metapneumovirus (HMPV) or parainfluenza virus type 3 (PIV-3). If a reduction in viral growth was observed in cells overexpressing a particular TRIM protein compared to a control cell line (overexpressing a protein with no antiviral activity), the role of the TRIMs was explored further. The results from this screen indicated that TRIM16 was able to restrict the growth of all three viruses tested, while TRIM69 was able to restrict the growth of RSV and HMPV. Subsequent analysis showed that both TRIM proteins restricted virus replication at the early stages of infection (i.e prior to synthesis of viral proteins within infected cells). Knockdown approaches further confirmed the antiviral role of endogenous TRIM16 and TRIM69 proteins. Currently, experiments are underway to determine their mechanism of antiviral action.
These findings are significant as they will equip us with the knowledge needed to design therapeutic compounds targeting antiviral TRIM proteins.