Discovery of new Covid infection mechanism provides clue to Covid leap to humans

The original SARS-CoV-2 viral strain that emerged in early 2020 was able to hold onto sugars known as sialic acids, which are found on the surface of human cells, an ability that later strains failed to retain.

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

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

Subsequent variants of concern, such as Delta and Omicron, lack this ability to grab sialic acid and rely on receptors on their crown spikes 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 investigate further. Using a nuclear magnetic resonance (NMR) spectroscopy technique called saturation transfer difference, they developed a new, advanced analysis method to tackle the complex problem. They have called the technique Universal Saturation Transfer Analysis (uSTA).

Professor Ben Davis of the Rosalind Franklin Institute and the University of Oxford, one of the senior authors of the paper, said: “Two of the continuing mysteries of the coronavirus pandemic are the mechanisms behind viral transmission and the origin of the zoonotic jump.

“There is some evidence that some flu viruses can seize sialic acid on the surface of human host cells, and this has been observed in Middle East Respiratory Syndrome (MERS), a coronavirus. Although SARS-CoV-2 variants of concern had not demonstrated this mechanism, our research shows that the viral strain that emerged in early 2020 could use it as a way to get into human cells.”

The binding mechanism is at the end of the N-terminal domain, a part of the virus that evolves faster. The domain has previously been implicated in the binding of sialic acid, but until the Rosalind Franklin Institute team applied high-resolution precision imaging and analysis, this had not been proven.

As to why the virus ditched its sugar-binding function as it evolved into new variants, Professor Davis hypothesizes that it may be needed for the first zoonotic leap in humans from animals, but can then be hidden until needed again — especially if the property is generally detrimental to the virus’s mission of replication and infection in humans.

The finding is consistent with evidence from the first wave in Italy. The Italian Genomics Consortium saw a link between the severity of COVID-19 disease and genetics, as patients with a particular gene mutation — one that affects the type of sialic acid on cells — were underrepresented in intensive care units. This suggested that the virus could infect some genotypes more easily than others.

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

“The new technique could be used by others to shed light on other viral structures and answer highly detailed questions. This work is an example of the unique technologies that the Rosalind Franklin Institute has developed to develop.”

The Rosalind Franklin Institute

The Rosalind Franklin Institute is a national institution dedicated to transforming life science through interdisciplinary research and technological development. The Institute brings together researchers from the fields of life, science and engineering to develop groundbreaking new technologies designed to address major challenges in health and life sciences.

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

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

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