The SARS-CoV-2 virus is around 100 nm in diameter, meaning 100 of these viruses would not fully stretch across a human hair when laid out in a row. It is easy to think about something so small, floating around and being absorbed into human cells, without considering that there are discrete interactions going on at every stage of viral infection in humans. Virus particles do not get passively absorbed into cells, there are many mechanical processes that must happen to allow the SARS-CoV-2 virus to physically dock with a human cell and initiate an internalisation process, much like spaceships docking in orbit.
Understanding these mechanisms is key to understanding how the virus replicates, spreads, and causes disease. They occur on such a small scale that they can be difficult to examine without the use of cutting-edge tools and techniques, like those available at Diamond.
Two publications have used facilities at Diamond to understand how the SARS-CoV-2 virus spreads and also how complications arise when mimicking the virus in vaccines.
A study published in Nature Communications used multiple techniques to reveal that the SARS-CoV-2 virus completely re-organises the cell when replicating and preparing to release. The study used a correlative approach, meaning that they were able to use different techniques to image the same sections of the infected cells. This ultimately yielded a lot more information than would be possible by using the techniques individually. The correlative approach also allowed the researchers to look at the infected cells on different spatial scales. They could look at whole cells as well as zooming in to very well-defined sections. This allowed them to build up a much more complete view of the COVID infection process.
The research team used Diamond’s electron Bio-Imaging Centre (eBIC) and combined cryo-electron microscopy and soft X-ray cryo-tomography at beamline B24 to show that the invasion of human cells by SARS-CoV-2 is extremely well organised and efficient. Importantly, the research team saw that virus replication and assembly was confined to very localised compartments within the cell, which explains how the virus replicates so efficiently. Each stage that the researchers were able to capture, from genome replication to the virus escaping the cell, involves a number of critical mechanical steps. If these steps are interrupted, then viral replication and spread could be stopped. Therefore, understanding these mechanisms will help us to find new drugs and treatments for COVID.
This video animation shows how the SARS-CoV-2 virus infection mechanism works at the cellular level. Copyright Diamond Light Source.
Another study published in Science Advances looked to understand what mechanical interactions could be causing the blood clots associated with some vaccines. For this they focused on adenoviruses, which are used by the virus to transmit SARS-CoV-2 proteins in the body during infection. The adenovirus can be injected safely and present SARS proteins to the immune system and prepare it for when a real SARS virus comes along and giving the patient immunity.
However, studies revealed that in certain patient groups, there was an autoimmune response against one of their own proteins called PF4. This autoimmune response was the reason that they were developing blood clots. Scientists used data collected at Diamond’s I03 Macromolecular Crystallography (MX) beamline as well a vast database from previous experiments to run simulations. They found that an adenovirus protein was latching on to the human PF4. This meant that when the immune system created a response to the virus, it was also creating a response to the human protein PF4. The simulations that were run can help researchers avoid this kind of adverse reaction in the future.
Cartoon representation of a proposed mechanism by which ChAdOx1 association with PF4 might result in thrombotic thrombocytopenic syndrome.
Image reused from DOI: 10.1126/sciadv.abl8213 under the CC BY 2.0 license.
COVID-19 is a disease involving numerous mechanical interactions. Likewise, the treatments for the disease involve more mechanical interactions with the human body in order to block the virus. Investigating and understanding these interactions at the molecular level using facilities like Diamond is essential to providing new vaccines and drugs to combat the global pandemic.
You can read the latest research with involvement from Diamond on the Omicron variant here.
eBIC (the UK's national cryo-EM facility) provides scientists with state-of-the-art experimental equipment and expertise in the field of cryo-electron microscopy. To find out more about eBIC, or to discuss potential applications, please contact Peijun Zhang: email@example.com
L Mendoça et al. Correlative multi-scale cryo-imaging unveils SARS-CoV-2 assembly and egress. Nature Communications 12. (July 2021). DOI: 10.1038/s41467-021-24887-y
Baker A.T. et al. ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome. Science Advances Vol 7, 49. (Dec 2021). DOI: 10.1126/sciadv.abl8213
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