Even 2.5 years afterits emergence, SARS‐CoV2 isstill a global disease impacting millions of lives where new variants appear to influence the efficacy of vaccines dramatically. It is therefore key to understand the underlying mechanism of both infection and to test potential antiviral treatments.
During infection, SARS‐CoV‐2 rearranges host cell membranes, forming large amounts of double‐membraned vesicular structures (DMVs) in the cytosol, termed replication complexes (RC). Inside, the viral genome is replicated before being packaged into new viral particles. We have found that a small fatty acid, Linoleic Acid (LA), is able to bind with high affinity to the Spike protein of SARS‐CoV‐2 (Toelzer et al., 2020). Upon binding, LA traps Spike in a non‐infectious, “closed” conformation and inhibits interactions with the receptor of the human host cell, thus providing an avenue for antiviral therapy. Besides this direct effect on binding, we (collaboration between the Verkade, Berger‐ Schaffitzel, and Davidson groups) have found that viruses that do manage to infect LA‐treated cells produce DMVs and new viruses that are misshapen as shown by electron microscopy (see Figure, Toelzer et al., 2022). Also, the number of viruses produced per cell is lower.
LA treatment generates droplets in the cell, and when infected with the SARS‐ CoV‐2 virus there appeared to be direct connections between these droplets and the DMV’s that are packaging new virus particles. Therefore, we hypothesise that LA may inhibit the membrane remodelling induced by the virus, suppressing the formation of RCs. LA thus may interfere with an essential step in viral replication which is conserved across coronaviruses and SARS‐CoV‐2 variant‐ independent. Recently we found that other free fatty acids (FFA) such as Oleic Acid have a similar effect. This project aims to elucidate the mechanism of FFA‐treatment on SARS‐CoV‐2 infection and replication. As a successful candidate you will work in a highly interdisciplinary environment between the groups of Professor Andrew Davidson, a specialist in coronavirus biology, Professor Christiane Berger‐ Schaffitzel, a cryo‐EM expert and Professor Paul Verkade, cell biologist and imaging expert. Focussed around state‐of‐the‐art imaging approaches such as cryogenic electron microscopy (EM), 3D electron tomography, and correlative light electron microscopy (CLEM) and using uniquely available fluorescent coronavirus and expertise in virus biology, you will aim to elucidate the molecular mechanism of action of FFA and collaborate on this very exciting area of research.
Our aim as the SWBio DTP is to support students from a range of backgrounds and circumstances. Where needed, we will work with you to take into consideration reasonable project adaptations (for example to support caring responsibilities, disabilities, other significant personal circumstances) as well as flexible working and part‐time study requests, to enable greater access to a PhD. All our supervisors support us with this aim, so please feel comfortable in discussing further with the listed PhD project supervisor to see what is feasible.
Information on “How to Apply” is available here: https://www.swbio.ac.uk/programme/projects-available/. When applying to the University of Bristol, please use the following link: Start your application | Study at Bristol | University of Bristol. To choose the correct programme, please start to type 'South West' in the search box and the SWBio programme will appear. When making your application, please indicate the supervisor name and the project title on the form. Ensure you provide all supporting documents as per the programme admissions statement.
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