Utrecht University: Corona infection occurs in deeper lung parts

The spikes of the SARS-CoV-2 virus attach best to the cells deeper in the lungs. This is the conclusion of pharmaceutical researchers at Utrecht University who assembled trimeric spikes. They did not suffice with using only the single monomer parts of those spikes. Last week, PLOS Pathogens published their findings.

Binding in the bronchioles
First author Kim Bouwman of Utrecht University sheds light on the research outcomes: “In the lungs of ferrets and hamsters, we found the highest binding activity of SARS-CoV-2 in the bronchioles, the second branching of the trachea. In higher parts of the respiratory tract the virus is probably less pathogenic. This corresponds to wat doctors see in patients that are hospitalized with a SARS-CoV-2 infection: the patients most severe cases cope with infections deep in their respiratory tracts.”

Cross section of a SARS-CoV-2 virus particle with its spikes. Illustration: Peiris, Guan & Yuen (2004)
A coronavirus particle is in fact a tiny globule containing, safely stored, the genetic material in the form of RNA. On the outer surface of the globule, spikes are present that can bind to the outer surface of an animal cell like the ones of humans, thereby possibly leading to an infection. The spikes bind stronger in one animal species compared to the other, and within a species, differences occur between organs as well.

The three identical spike proteins embrace each other with both arms, like a group hug.
Trinity of monomers
That difference in infection rate is strongly related to the effectiveness in which the spikes attach themselves to receptors on the host cell. Bouwman compares it with the way Velcro works. “The size, structure and shape of the hairs on both sides determine how well it sticks.”

Every spike on a coronavirus particle consists of three identical spike proteins, which are folded around each other and embrace each other with both their arms like in a group hug. “It is a trinity of momoners,” says Bouwman. “Currently, labs that conduct research on the spike proteins often use the separate monomers or dimers. Only few of them assemble trimers.”

Trinity of monomers of a SARS-CoV-2 spike. Illustration: McCallum, Walls & Bowen (2020)
For research on the infection rate of the virus, it appears to be best to work with the conformation of the spike proteins that is found on the virus. “In our paper we demonstrate that trimers of the spike bind much better to cell lines or the lungs of ferrets and hamsters than monomers do. Our proteins enable us to visualise which cells can be bound by these proteins and where the virus may infect its host.”

Fundamental research directed by current affairs
The reason that labs still work with monomers instead of trimers is historic, according to Bouwman. “In 2003, during the first SARS-CoV epidemic in China, researchers worked with monomers or dimers of spike proteins, as making trimers was really hard at the time. In the end, it didn’t lead to a real pandemic and labs stopped their spike research. Since the beginning of 2020, labs worldwide have taken up the research again, and they all use the method they used previously. But I, too, have developed my own method during my PhD research: I used parts of spike proteins that are made as trimers. So now I could apply that perfectly.”

“For the development and testing of possible neutralising antibodies, pharmaceutical scientists should use the spikes as trimers in their research.”

Kim Bouwman, pharmaceutical researcher UU
Last September, Bouwman defended her dissertation at the Utrecht Faculty of Veterinary Science, department of pathology, on the interactions between coronaviruses and birds as their hosts. “At the Institute of Pharmaceutical Sciences, I am now, driven by current events, conducting fundamental research on the interaction of SARS-CoV-2 with different cell types in different animal species.”

In the currently used vaccines, the spikes are present as trimers instead of monomers. Bouwman: “So for the development and testing of possible neutralising antibodies, it is very relevant for pharmaceutical scientists to use the spikes as trimers in their research.”