Investigating the role of novel RNA-binding protein TRIM25 in viral nucleic acids sensing and signalling.

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RNA viruses are an important class of pathogen that continue to cause devastating epidemics in the 21st century. Taking IAV as an exemplar, it threatens periodic pandemics, kills 250,000 to 500,000 people annually even in epidemic phases, generating a significant socioeconomic burden ($20 billion dollars in every year in the US alone). The impact of IAV infections on livestock animals is equally tremendous. During a 2005 bird flu outbreak the total economic losses in South East Asia alone were calculated at around $10 billion. However, we still do not know all of the molecular mechanisms of key host proteins that sense and restrict human and animal IAV infections. The first line of cellular defence against these types of virus is the innate immune system. Few RNA viruses, including IAV, produces RNA molecules that are recognised by cellular proteins that trigger the anti-viral response. TRIM25 is a key host protein factor in this process that was proposed to enable robust innate immune response to RNA viruses by activating key host pathogen recognition receptors. Using our expertise in RNA biology we discovered that TRIM25 binds to host RNA and regulates its stability. Despite this, direct binding of TRIM25 to IAV RNAs and its detailed function in innate immune response have not yet been described.Our preliminary data suggests that TRIM25 binds directly to IAV RNA and that it restricts the virus using pathogen recognition receptor-independent mechanism. Moreover, we show that Trim25s from livestock animals reduced RNA-binding potential when compared to human TRIM25. This could manifest itself with weaker antiviral functions of livestock Trim25s. With this project, we aim to take advantage of an assembled multi-disciplinary team to exploit these novel findings to uncover the role of the RNA-binding activity of TRIM25 in the antiviral response to IAV infection. We will dissect the RNA-binding roles of TRIM25 in response to IAV in human and animal cells. The outcome of this research will reveal how TRIM25 uses its RNA-binding activity for anti-viral functions. Importantly, TRIM25 belongs to a large (> 80 members) family of tripartite motif-containing proteins. They have various functions in cellular processes and disease, including development, apoptosis, autophagy, carcinogenesis and innate immunity. Thus, our research will open new lines of investigations into other TRIM proteins and their putative RNA-binding roles. Overall, our project has the potential to make crucial contributions to understanding the innate immune response to IAV and provide a platform for the development of novel, RNA-based antiviral therapeutics and livestock animals more resistant to RNA viruses.