Discovery of new Covid infection mechanism offers clue to Covid’s leap to humans

The original SARS-CoV-2 viral strain that emerged in early 2020 was able to latch onto sugars called sialic acids, found on the surface of human cells, an ability later strains did not retain.

This bond was found using a combination of extremely precise magnetic resonance and high-resolution imaging, conducted at the Rosalind Franklin Institute and the University of Oxford, and published in the journal Science this week.

This unique ability of the early strain also raises the possibility that this is how the virus first transferred from animals to humans.

Later variants of concern, such as Delta and Omicron, lack this ability to grab sialic acid and rely on receptors in their crown tips to attach to proteins called ACE2 on human cells.

An international team led by scientists from the Rosalind Franklin Institute used magnetic resonance and complex imaging techniques to further their research. Using a nuclear magnetic resonance (NMR) spectroscopy technique called saturation transfer difference, they developed a sophisticated new analytical method to solve the complex problem. They called the Universal Saturation Transfer Analysis (uSTA) technique.

Professor Ben Davis of the Rosalind Franklin Institute and the University of Oxford, one of the paper’s lead authors, said: “Two of the ongoing mysteries of the coronavirus pandemic are the mechanisms behind of viral transmission and the origins of zoonotic leap.

“There is evidence that some influenza viruses can grab sialic acid from the surface of human host cells, and this has been seen in Middle East Respiratory Syndrome (MERS), which is a coronavirus. Although the concerning variants of SARS-CoV-2 have not shown this mechanism, our research reveals that the viral strain that emerged in early 2020 could use it as a means of entering human cells.

The binding mechanism is at the end of the N-terminal domain, which is a faster-evolving part of the virus. The field has previously been implicated in sialic acid binding, but until the team at the Rosalind Franklin Institute applied high-resolution precision imaging and analysis, this remained unproven.

As to why the virus has discarded sugar-binding function as it evolved into new variants, Professor Davis hypothesizes that it may be necessary for the initial zoonotic leap in humans from animals, but can then be hidden away until needed again – particularly if the trait is largely detrimental to the virus’s mission to replicate and infect humans.

The finding correlates with evidence from the first wave in Italy. The Italian Genomics Consortium found a correlation between COVID-19 disease severity and genetics, as patients with a particular genetic mutation – one that affects the type of sialic acid on cells – were underrepresented in the intensive care units. This suggested that the virus found it easier to infect certain genotypes than others.

Professor James Naismith, Director of the Rosalind Franklin Institute, says: “Thanks to our ultra-high precision imaging and new method of analysis, we can see a previously unknown structure at the very end of the SARS peak. -CoV-2. Amazingly, our finding correlates with what the Italian researchers noted in the first wave, suggesting it was a key role in early infection.

“The new technique can be used by others to shed light on other viral structures and answer extremely detailed questions. This work is an example of the unique technologies that the Rosalind Franklin Institute was created to develop.

The Rosalind Franklin Institute

The Rosalind Franklin Institute is a national institute dedicated to transforming the life sciences through interdisciplinary research and technology development. The Institute brings together researchers in the life sciences, physical sciences and engineering, to develop new disruptive technologies designed to meet the great challenges of health and life sciences.

The Franklin is funded by UK Research and Innovation through the Engineering and Physical Sciences Research Council (EPSRC). The Institute is an independent organization founded by UK Research and Innovation, ten UK universities and Diamond Light Source, with its central hub at the Harwell Science and Innovation Campus.

The Rosalind Franklin Institute is a limited liability company registered in England and Wales, registration number 11266143. We are a registered charity, number 1179810.

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