In a recent work we showed that cellular RNA is massively degraded upon Sindbis virus infection, and this appears to apply to a broad range of cytopathic viruses. The goal of this project is to understand how cellular RNA degradation is triggered and what its consequences in infection are. We will focus on the exonuclease XRN1 that is stimulated upon the infection of several RNA viruses.
This project is a join effort between the Castello lab and the Pelechano‘s lab and combines cutting edge transcriptomic approaches with virology methods and computational biology.
If you are interested, you can apply to this project here:
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in December 2019 and is the virus responsible for the COVID-19 pandemic. Recent serological data from Spain and Germany have smashed the hopes of the scientific community on herd immunity in the mid-term, as only 10-15% of the people analysed presented antibodies against SARS-CoV-2. Hence, the development of a vaccine is urgently required. Oxford University scientists working at The Jenner Institute have developed a chimpanzee adenoviral vector vaccine encoding the SARS-CoV-2 spike glycoprotein, the club-shaped protein on the surface of the virus (visit our recent comments on the spike and the Oxford vaccine effort for more information). The vaccine, ChAdOx1 nCoV-19 is based on an adenoviral vector, a strategy previously used for the middle eastern respiratory syndrome coronavirus (MERS-CoV) vaccine that showed protection in non-human primates.
Initial testing of ChAdOx1 nCoV-19 in mice showed that injection of the vaccine into muscle tissue produced a strong antibody response against both subunits of the spike glycoprotein, mainly driven by T helper cells (Th1 type). These cells produce cytokines which are chemical messengers that signal to other immune cells in the body and generate a specific type of immune response. The antibodies produced in immunised mice were neutralising. This means that the binding of the antibody interferes with the ability of the viral spike glycoprotein to interact with the cell’s surface and enter into the cytoplasm.
Following the success in mice, the ChAdOx1 nCoV-19 vaccine was tested in rhesus macaques, which are closer to humans. 6 animals were vaccinated followed by challenge with a very high dose of SARS-CoV-2 28 days later. As quickly as 14 days later, neutralising antibodies against the spike glycoprotein were detected in the monkeys’ blood. When challenged with SARS-CoV-2, vaccinated monkeys showed very little respiratory stress symptoms when compared to unvaccinated controls. Viruses were produced in the nose of vaccinated and unvaccinated monkeys at a similar level. However, this is possibly due to the high virus dosage that they were exposed to, which does not reflect the levels a human would encounter in natural infection. The RNA genome of SARS-CoV-2 was detected in all control monkeys, but only in 2 out of 6 vaccinated monkeys. After 3 days, SARS-CoV-2 replication was detected in unvaccinated controls through the measurement of sub-genomic RNAs. However, replication was undetectable in vaccinated monkeys as no sub-genomic RNA was detected. Conversely to unvaccinated macaques, neither pneumonia nor immune-enhanced inflammatory disease was detected in vaccinated animals after 7 days post virus inoculum.
These results show that a single vaccination with ChAdOx1 nCoV-19 effectively prevents SARS-cov2-derived lung damage in monkeys despite high doses of virus inoculum. This data is very promising and will complement the results from the phase 1 clinical trials that began in Oxford on April 23rd 2020 and involve 1000 human volunteers. These results are a promising step towards the development of a safe and effective vaccine against SARS-CoV-2.
Written by Kate Dicker, WT IITM DPhil student
Original work: ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques. van Doremalen, N., Lambe, T., […], Gilbert, S.C., and Munster, V.J., 2020 BioRxiv. doi: https://doi.org/10.1101/2020.05.13.093195
Our Colleague Juan Reguera, offers a PhD student position at the Viral Macromolecular Complexes Teat at the AFMB in Marseille. The aim of the project is the structural and functional characterisation of retrotrasposon integration in yeast. Interested candidates can send their CV and a motivation letter to firstname.lastname@example.org