SARS-CoV-2 can attach to not one but two receptors on the host cell surfaces shows new Danish research.
In 2003, the SARS epidemic caused panic in 26 countries on six continents, but only slightly more than 8,000 people developed SARS, resulting in less than 1,000 deaths. Almost 20 years later, SARS-CoV-2 struck, with more than 186 million registered cases and 4 million deaths so far. The big question has therefore been why SARS-CoV-2 is transmitted far more effectively than SARS-CoV-1. A new study shows that one explanation is how it binds to human cells, report the Novo Nordisk Foundation.
“Our study shows that SARS-CoV-2 can bind to not one but two cell receptors. In addition to the known angiotensin-converting enzyme (ACE) receptor, SARS-CoV-2 can attach to sialic-acid receptors, mainly in cells in the upper airways. We think that SARS-CoV-2 uses them as a base from which it can quietly emerge. This knowledge both explains why SARS-CoV-2 is far more virulent than SARS-CoV-1 and is important for combatting its attacks,” says Tobias Weidner, Associate Professor, Department of Chemistry, Aarhus University.
Differences and similarities between coronaviruses
Seven coronavirus strains are known to infect people. In addition to the usual relatively harmless common cold viruses, in the past two decades, in addition to SARS-CoV-2, two other coronaviruses have caused three of the most severe epidemics: SARS-CoV-1 in 2003, the Middle East respiratory syndrome (MERS) in 2010 and the current COVID-19 pandemic.
“We therefore wanted to examine structural differences and similarities between these three viruses to try to understand the differences in both diffusion speed and mortality rates. We therefore used a new computational method to compare how well two protein surfaces interact. We could thus determine whether the coronaviruses differ in how well their surfaces interact with the surfaces of human cells,” says Weidner.
From the start of the COVID-19 pandemic, it was known that the virus enters cells to multiply by attaching to the ACE2 receptors on the membranes of many cells in the lungs, blood vessels, heart, kidneys and intestines. Normally, a person’s own enzymes connect to the cells, but the spike protein on SARS-CoV-2 can trick a cell into allowing the virus to attach itself.
“SARS-CoV-1 had the same ability, and SARS-CoV-2 has retained this. The spike protein from SARS-CoV-2 can also bind to another type of receptor: the sialic-acid receptors,” explains Weidner.
Can explain the latency in the development of symptoms
Unlike the ACE2 receptors, sialic acids are present on ciliated epithelial cells, primarily in the upper airways and in single cells in the lower airways – an ability that SARS-CoV-2 apparently shares with MERS.
“To confirm our computer calculations by Edoardo Milanettis team, we carried out an experiment in which we constructed some artificial cells called micelles. We therefore tested in a realistic system whether the differences found between SARS, MERS and COVID-19 could be proven in practice,” says Weidner.
The experiments confirmed the researchers’ assumptions. SARS-CoV-2 could bind to both receptors, and this makes very good sense, given its infectivity but also the latency between infection and symptoms and onward transmission.
“The fact that SARS-CoV-2 initially attaches to the sialic-acid receptors on the surface of cells in the upper airways makes perfect sense. Once it has gained a foothold there, it mostly moves to the lungs, where it attaches to the cells themselves through the ACE2 receptor. This can also largely explain the latency in the development of symptoms, which is a great benefit for SARS-CoV-2, since it can be transmitted without you knowing that you are ill,” explains Weidner.
The fact that SARS-CoV-2 is present on the surface of the cells in the upper airways is another fact that makes it more contagious, states the researchers. SARS-CoV-1 had to be coughed all the way up from the lungs to infect another person. SARS-CoV-2 simply needs to move from the upper airways to a new host via saliva, sneezing or possibly just exhaled air.
“Evidence indicates that the binding strength between SARS-CoV-2 and the various receptors is also absolutely crucial. The stronger SARS-CoV-2 binds, the more difficulty it has in moving further, either down into the lungs or onwards to another host that the virus can infect,” says Weidner.
The new knowledge on the ability of SARS-CoV-2 to bind to different receptors may prove absolutely crucial, because it explains how it acts and because this can provide important input for developing treatments.
“This knowledge is essential for developing medicine that can either prevent SARS-CoV-2 from binding to uninfected people or prevent onward transmission from infected people. For example, there is no point in just blocking the ACE2 receptor, since SARS-CoV-2 may simply lurk at the sialic acid receptor and wait for an ACE2 receptor to become free, enabling it to strike and infect again,” says Weidner.