A short sequence in the genome of SARS-CoV-2 — the virus that causes COVID-19 — provides the virus with an additional way to enter cells, and plays an important role in its transmissibility and infectiousness, a team of international collaborators, including researchers at UQ’s Queensland Brain Institute, have discovered.
A virus’ ability to invade tissues is determined by its interaction with particular receptors on the surface of cells in the body.
Specifically, the ‘spike’ proteins on the surface of the virus enables it to recognise these receptors and use them to gain entry to host cells.
Receptor the gateway for coronavirus
It’s known that the virus that caused SARS (SARS-CoV) in 2003 and the new coronavirus that causes COVID-19 (SARS-CoV-2) both use the ACE2 receptor to enter into human cells.
The ACE2 receptor is found on the surface of a variety of cells in the human body, including cells found in the lower respiratory tract, the gastrointestinal tract, and other organs such as the kidney.
Yet SARS-CoV-2 is more infectious than SARS-CoV and able to invade human tissues more extensively, including those in the upper airways, from where the virus readily sheds via coughing and sneezing. The reason for this virus being more infectious was previously unknown.
When the genomic sequence of SARS-CoV-2 became available at the end of January 2020, virologists were struck by the presence of a short sequence of amino acids, known as the ‘furin cleavage site’ on the spike protein.
This site is also present in several highly pathogenic human viruses, including another coronavirus, MERS. It had been proposed that this acquired extra sequence might play a role in the high transmissibility and infectiousness of SARS-CoV-2 — but how?
Twin receptors maximise coronavirus' infectious potential
Now, the team of international collaborators have discovered that this short sequence enables SARS-CoV-2 to enter cells via an additional cellular receptor called neuropilin-1 (NRP1).
According to the study, now published in the journal Science, when cells have both ACE2 and NRP1 the virus reaches its maximum infectious potential.
Because NRP1 is found on a variety of tissue types including those in the upper airways, this could explain why SARS-CoV-2 is more infectious and more extensively invasive than SARS.
The study’s senior authors, Dr Giuseppe Balistreri of the University of Helsinki in Finland and Professor Mikael Simons of the Technical University of Munich in Germany, worked with collaborators in Finland, Germany and Australia, including Professor Frederic Meunier from UQ’s Queensland Brain Institute.
Together, they showed that the NRP1 receptor is found at particularly high levels on cells in the nasal cavity. By analysing samples from deceased COVID-19 patients, they also showed that the virus was particularly prevalent in cells that have NRP1 on their surface.
Coronavirus "affects our brain cells"
Intriguingly, these cells included the cells that give rise to olfactory sensory neurons, which are present in the lining of the nose and allow us to continuously regenerate the sense of smell — a sense that is reported to be lost in some cases of COVID-19.
“The fact that antibodies blocking Neuropilin-1 are able to block infection by forty per cent, strongly suggests that this pathway is key for the virus’ infectivity,” said Dr Giuseppe Balistreri.
Professor Frederic Meunier said, “There is very little doubt that SARS-CoV-2 affects our brain cells and the long-term consequences are not yet known.”
“The discovery that NRP1 binds the spike opens the door to in-depth research into the virus' neurotropism – its ability to infect nerve tissue — as well as new therapeutic avenues,” he added.
Interestingly, an independent team led by scientists at the University of Bristol (UK) and including University of Queensland structural biologists Professor Brett Collins, confirmed that the viral spike directly binds NRP1, nicely complementing this study.
This research was the result of extraordinary international collaboration and largely occurred during the shut-downs due to the pandemic. Dr Merja Joensuu from the Queensland Brain Insitute was a key collaborator on the neuroscience and microscopy elements of the research.
