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In people infected with SARS-CoV-2, different variants could be hidden in different parts of the body.

People suffering from COVID-19 could have several different SARS-CoV-2 variants hidden from the immune system in different parts of the body, finds a new study published in nature communication by an international research team. The study’s authors say this can make it significantly more difficult to completely clear the virus from an infected person’s body through their own antibodies or through therapeutic antibody treatments.

COVID-19 continues to sweep across the globe, causing hospitalizations and deaths, harming communities and economies worldwide. Successive variants of concern (VoC) replaced the original Wuhan virus and increasingly evaded immune protection from vaccination or antibody treatments.

In new research, consisting of two parallel published studies in nature communicationan 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, the two directors of the Max Planck Bristol Center for Minimal Biology show how the virus can develop differently in different cell types and adapt its immunity in the same infected host.

The team wanted to study the function of a tailored pocket in the SARS-CoV-2 spike protein in the virus’ infection cycle. The bag spotted by the Bristol team in one earlier breakthroughplayed an essential role in viral infectivity.

“An incessant series of variants has now completely replaced the original virus, with Omicron and Omicron 2 dominating worldwide,” said Professor Imre Berger. “We analyzed an early variant discovered in Bristol, BrisDelta. It had changed shape from the original virus, but the pocket we discovered was unchanged.” Interestingly, BrisDelta presents as a small subpopulation in the patient samples, but appears to infect certain cell types better than the virus that infected the first Infection wave dominated.

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

The team applied cutting-edge synthetic biology techniques, cutting-edge imaging and cloud computing to decipher viral mechanisms at work. To understand the pocket’s function, the scientists built synthetic SARS-CoV-2 virions in the test tube, which mimic the virus but have the major advantage of being safe because they don’t replicate inside human cells.

With the help of these artificial virions, they were able to study the precise mechanism of the pocket during viral infection. They showed that upon binding of a fatty acid, the spike protein that decorates the virions changed shape. This “shape” switching mechanism effectively camouflages the virus from the immune system.

dr Oskar Staufer, first author of this study and joint member of the Max Planck Institute in Heidelberg and the Max Planck Center in Bristol, explains: “By ‘crouching down’ the spike protein when binding inflammatory fatty acids, the virus becomes less visible to them Immune system. This could be a mechanism to avoid host recognition and a strong immune response over a longer period of time and increase overall infection efficiency.”

“It appears that having this pocket built specifically to recognize these fatty acids gives SARS-CoV-2 an advantage in the body of infected people because it can multiply so quickly. This could explain why it is present in all variants, including Omicron,” Professor Berger added. “Interestingly, the same feature also gives us a unique opportunity to defeat the virus precisely because it’s so conserved – with a tailored antiviral molecule that blocks the pocket.” Halo Therapeuticsa University of Bristol spin-out recently founded by the authors is taking exactly this approach to develop pocket-binding pan-coronavirus antivirals.

The team consisted of experts from the Bristol UNCOVER Group, the Max Planck Institute for Medical Research in Heidelberg, Germany, spin-off from the University of Bristol Halo Therapeutics Ltd and other employees in the UK and Germany. The studies were funded by the Max Planck Societythe Welcome trust and the European Research Council, with additional support from Oracle for research for powerful cloud computing resources. The authors thank the Elizabeth Blackwell Institute, University of Bristol for generous support.

Papers:

Structural insights into cell-type specific evolution of intra-host diversity by SARS-CoV-2” by K. Gupta et al nature communication

Synthetic virions show fatty acid-coupled adaptive immunogenicity of the SARS-CoV-2 spike glycoprotein. by O. Staufer et al nature communication

Binding pocket for free fatty acids in the closed structure of the SARS-CoV-2 spike protein‘ by C Toelzer et al. in Science.

Further information

Discovery of the stun bag
The discovery of a drug-ready pocket in the SARS-CoV-2 spike protein is explained in a YouTube video and at A science podcast. A press release about the SARS-CoV-2 synthetic virion project was issued by the Max Planck Society and is available Here.

About Professor Imre Berger
Imre Berger is also Director of BrisSynBio, a BBSRC/EPSRC synthetic biology research center 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 Executive Director of the Max Planck Institute for Medical Research in Heidelberg, Germany, Professor of Biophysical Chemistry at the University of Heidelberg and speaker of Max Planck School Matter to Life.

About the Max Planck Bristol Center
The Max Planck Bristol Center (MPBC) is a joint research center of the Max Planck Society and the University of Bristol. The MPBC focuses on the field of synthetic and minimal biology. Based in Bristol and with hubs at the Max Planck Institutes in Martinsried, Mainz and Heidelberg, MPBC scientists aim to construct nanoscale artificial cells, cytoskeletons and molecular machines to create the building blocks necessary for life and their… examine applications.

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

Bristol UNCOVER is supported by the Elizabeth Blackwell Institute
Learn about the institute’s COVID-19 research in five key areas: viral natural history, therapeutics, and diagnostics research; epidemiology; clinical management; vaccinations; and ethics and social sciences.

About Halo Therapeutics Ltd
Halo Therapeutics is a University of Bristol spinout developing safe, self-administered pan-coronavirus prophylactics and early-stage antiviral treatments. Halo Therapeutics Ltd is based at Science Creates St Phillips Central, Andrew Road, Bristol, UK.

About Oracle for Research
Oracle for Research is a global community working to tackle complex problems and drive meaningful change in the world. The program offers scientists, researchers, and academic innovators high-quality, cost-effective cloud technologies, participation in the Oracle Research User Community, and access to Oracle’s technical support network. The program’s free cloud credits allow users to leverage Oracle’s proven technology and infrastructure while keeping research-developed intellectual property private and secure. Learn more at https://www.oracle.com/oracle-for-research/ and https://twitter.com/OracleResearch/.

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