New research shows virus plays ultimate game of ‘hide and seek’ with immune system

Newswise — People suffering from COVID-19 could have several different SARS-CoV-2 variants hidden away from the immune system in different parts of the body, finds new research published in Nature Communications by an international research team.  The study’s authors say that this may make complete clearance of the virus from the body of an infected person, by their own antibodies, or by therapeutic antibody treatments, much more difficult.  

COVID-19 continues to sweep the globe causing hospitalisations and deaths, damaging communities and economies worldwide.  Successive variants of concern (VoC), replaced the original virus from Wuhan, increasingly escaping immune protection offered by vaccination or antibody treatments.

In new research, comprising two studies published in parallel in Nature Communications, an international team led by Professor Imre Berger at the University of Bristol and Professor Joachim Spatz at the Max Planck Institute for Medical Research in Heidelberg , both Directors of the Max Planck Bristol Centre of Minimal Biology, show how the virus can evolve distinctly in different cell types, and adapt its immunity, in the same infected host.

The team sought to investigate the function of a tailor-made pocket in the SARS-CoV-2 spike protein in the infection cycle of the virus. The pocket, discovered by the Bristol team in an earlier breakthrough, played an essential role in viral infectivity.

“An incessant series of variants have completely replaced the original virus by now, with Omicron and Omicron 2 dominating worldwide.” said Professor Imre Berger. “We analysed an early variant discovered in Bristol, BrisDelta. It had changed its shape from the original virus, but the pocket we had discovered was there, unaltered”. Intriguingly, BrisDelta, presents as a small subpopulation in the samples taken from patients, but appears to infect certain cell-types better than the virus that dominated the first wave of infections.

Dr Kapil Gupta, lead author of the BrisDelta study, explains: “Our results showed that one can have several different virus variants in one’s body. Some of these variants may use kidney or spleen cells as their niche to hide, while the body is busy defending against the dominant virus type. This could make it difficult for the infected patients to get rid of SARS-CoV-2 entirely.”

The team applied cutting-edge synthetic biology techniques, state-of-the-art imaging and cloud computing to decipher viral mechanisms at work. To understand the function of the pocket, the scientists built synthetic SARS-CoV-2 virions in the test tube, that are mimics of the virus but have a major advantage in that they are safe, as they do not multiply in human cells.

Using these artificial virions, they were able to study the exact mechanism of the pocket in viral infection. They demonstrated that upon binding of a fatty acid, the spike protein decorating the virions changed their shape. This switching ‘shape’ mechanism effectively cloaks the virus from the immune system.

Dr Oskar Staufer, lead author of this study and joint member of the Max Planck Institute in Heidelberg and the Max Planck Centre in Bristol, explains: “By ‘ducking down’ of the spike protein upon binding of inflammatory fatty acids, the virus becomes less visible to the immune system. This could be a mechanism to avoid detection by the host and a strong immune response for a longer period of time and increase total infection efficiency.”

“It appears that this pocket, specifically built to recognise these fatty acids, gives SARS-CoV-2 an advantage inside the body of infected people, allowing it to multiply so fast. This could explain why it is there, in all variants, including Omicron” added Professor Berger. “Intriguingly, the same feature also provides us with a unique opportunity to defeat the virus, exactly because it is so conserved - with a tailormade antiviral molecule that blocks the pocket.”  Halo Therapeutics, a recent University of Bristol spin-out founded by the authors, pursues exactly this approach to develop pocket-binding pan-coronavirus antivirals.

The team included experts from Bristol UNCOVER Group, the Max Planck Institute for Medical Research in Heidelberg, Germany, Bristol University spin-out Halo Therapeutics Ltd and further collaborators in UK and in Germany.  The studies were supported by funds from the Max Planck Gesellschaft, the Wellcome Trust and the European Research Council, with additional support from Oracle for Research for high-performance cloud computing resources. The authors are grateful for the generous support by the Elizabeth Blackwell Institute of the University of Bristol.

Papers

‘Structural insights in cell-type specific evolution of intra-host diversity by SARS-CoV-2’ by K Gupta et al in Nature Communications

‘Synthetic virions reveal fatty acid-coupled adaptive immunogenicity of SARS-CoV-2 spike glycoprotein’ by O Staufer et al in Nature Communications

‘Free fatty acid binding pocket in the locked structure of SARS CoV-2 spike protein’ by C Toelzer et al in Science.

Notes to editors:

For further information or to arrange an interview with Professor Imre Berger, please contact Shona East/Victoria Tagg[Mon to Wed], email [email protected], [email protected] or Caroline Clancy [Wed to Fri], email [email protected], mobile: +44 (0)7776 170238 at the University of Bristol.

Images/video

Movie: Spike protein structure from BrisDelta, an early SARS-CoV-2 variant discovered in Bristol is available to download here. Credit: Christine Toelzer, University of Bristol

Image: Image of human epithelial cells (green with blue nuclei) are incubated with synthetic SARS-CoV-2 virions (magenta) to study infection and immune evasion is available to download here. Credit: Oskar Staufer and MPI for Medical Research, Germany

Druggable pocket discovery

The discovery of a druggable pocket in the SARS-CoV-2 Spike protein is explained in a YouTube video and in a Science podcast. A press release about the synthetic SARS-CoV-2 virion project has been issued by the Max Planck Society and is available here.

About Professor Imre Berger

Imre Berger is also Director of BrisSynBio, a BBSRC/EPSRC Research Centre for Synthetic Biology in Bristol, Co-Director of the Bristol BioDesign Institute, Wellcome Trust Investigator and ERC Investigator, and CSO of Halo Therapeutics Ltd.

About Professor Joachim Spatz

Joachim Spatz is also Managing Director of the Max Planck Institute for Medical Research in Heidelberg, Germany, Professor of Biophysical Chemistry at the University of Heidelberg and Speaker of the Max Planck School Matter to Life.

About the Max Planck Bristol Centre

The Max Planck Bristol Centre (MPBC) is a joint research centre of the Max Planck Society and the University of Bristol. The  MPBC is focused on the field of synthetic and minimal biology. Located in Bristol and with nodes at Max Planck Institutes in Martinsried, Mainz and Heidelberg, scientists in the MPBC aim to construct artificial cells, cytoskeletons and nanoscale molecular machines to investigate the building blocks necessary for life and their applications.

Study collaborators at University of Bristol

University of Bristol collaborators on the project include: Professor Adrian Mulholland and his team in the School of Chemistry, who worked on the molecular dynamics simulations and Professor Andrew Davidson and his team in the School of Cellular and Molecular Medicine who discovered BrisDelta and its preference to infect and propagate in distinct cell types.

About coronavirus (SARS-CoV-2) The surface of the coronavirus particle has proteins sticking out of it known as Spike proteins which are embedded in a membrane.  They have the appearance of tiny little crowns, giving the virus its name (corona). Inside the membrane is the viral genome wrapped up in other proteins. The genome contains all the genetic instruction to mass produce the virus. Once the virus attaches to the outside of a human cell, its membrane fuses with the human cell membrane and its genetic information into the human cell.  Next, the virus instructs the cell to start replicating its genome and produce its proteins. These are then assembled into many new copies of the virus which, upon release, can infect many more cells. The viral proteins play diverse further roles in coronavirus pathology.

Bristol UNCOVER Group In response to the COVID-19 crisis, researchers at the University of Bristol formed the Bristol COVID Emergency Research Group t(UNCOVER) to pool resources, capacities and research efforts to combat this infection. Bristol UNCOVER includes clinicians, immunologists, virologists, synthetic biologists, aerosol scientists, epidemiologists and mathematical modellers and has links to behavioural and social scientists, ethicists and lawyers. Follow Bristol UNCOVER on Twitter at: twitter.com/BristolUncover

For more information about the University of Bristol’s coronavirus (COVID-19) research priorities visit: www.bristol.ac.uk/research/impact/coronavirus/research-priorities/

Find out how you can support their critical work.

Bristol UNCOVER is supported by the Elizabeth Blackwell Institute Find out more about the Institute’s COVID-19 research looking into five key areas: virus natural history, therapeutics and diagnostics research; epidemiology; clinical management; vaccines; and ethics and social science.

About Halo Therapeutics Ltd

Halo Therapeutics is a University of Bristol spin-out developing safe, self-administered pan-coronavirus prophylactics and early antiviral treatments. Halo Therapeutics Ltd is located at Science Creates St Philipps Central, Andrew Road, Bristol, UK.

About Oracle for Research

Oracle for Research is a global community that is working to address complex problems and drive meaningful change in the world. The program provides scientists, researchers, and university innovators with high-value, cost-effective Cloud technologies, participation in Oracle research user community, and access to Oracle’s technical support network. Through the program’s free cloud credits, users can leverage Oracle’s proven technology and infrastructure while keeping research-developed IP private and secure. Learn more at https://www.oracle.com/oracle-for-research/ and https://twitter.com/OracleResearch/. 

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