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Sanger Institute researchers help identify the nose cells that act as entry points for the Covid-19 virus




Wellcome Sanger Institute scientists have helped to identify two specific cell types in the nose that are likely initial infection points for the Covid-19 virus.

The study could help to explain why it has such a high transmission rate - and reveals potential targets for tackling the problem.

This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses. Note the spikes that adorn the outer surface of the virus, which impart the look of a corona surrounding the virion, when viewed electron microscopically. A novel coronavirus, named Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China in 2019. The illness caused by this virus has been named coronavirus disease 2019 (COVID-19). Picture: Alissa Eckert, MS; Dan Higgins, MAMS; CDC (34140158)
This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses. Note the spikes that adorn the outer surface of the virus, which impart the look of a corona surrounding the virion, when viewed electron microscopically. A novel coronavirus, named Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China in 2019. The illness caused by this virus has been named coronavirus disease 2019 (COVID-19). Picture: Alissa Eckert, MS; Dan Higgins, MAMS; CDC (34140158)

The researchers discovered that goblet and ciliated cells in the nose have high levels of entry proteins that the virus uses to get into our cells. They also found that cells in the eye and some other organs contain viral-entry proteins.

The study, published in Nature Medicine, also predicts how a key entry protein is regulated with other immune system genes.

The work is part of the ongoing international effort to use data from the Human Cell Atlas (HCA) - the project creating reference maps of all human cells - to understand infection and disease.

It is the first publication with the Lung Biological Network - a consortium of 71 scientistscollaborating to map the airway cells in our body.

Dr Sarah Teichmann, a senior author from the Wellcome Sanger Institute and co-chair of the HCA organising committee, said: “As we’re building the Human Cell Atlas, it is already being used to understand Covid-19 and identify which of our cells are critical for initial infection and transmission.

“This information can be used to better understand how coronavirus spreads. Knowing which exact cell types are important for virus transmission also provides a basis for developing potential treatments to reduce the spread of the virus.”

The SARS-CoV-2 virus that causes Covid-19 uses a similar mechanismto infect our cells as the related coronavirus that caused the 2003 SARS epidemic.

A spike on the outside of the virus acts like a key to unlock an ACE2 (angiotensin converting enzyme II) receptor protein on the human cell.

A second protein inside the cell – known as the TMPRSS2 protease – is then used to complete entry, which then allows the virus to reproduce and transmit itself.

Dr Sarah Teichmann FMedSci, Cellular Genetics Programme Head, WTSI,in front of the computer cluster at Sanger. Picture: Pari Naderi. (34150962)
Dr Sarah Teichmann FMedSci, Cellular Genetics Programme Head, WTSI,in front of the computer cluster at Sanger. Picture: Pari Naderi. (34150962)

However, until now the exact cell types involved in the nose had not previously been confirmed.

Dr Waradon Sungnak, the first author on the paper from Wellcome Sanger Institute, said: “We found that the receptor protein - ACE2 - and the TMPRSS2 protease that can activate SARS-CoV-2 entry are expressed in cells in different organs, including the cells on the inner lining of the nose.

“We then revealed that mucus-producing goblet cells and ciliated cells in the nose had the highest levels of both these Covid-19 virus proteins, of all cells in the airways. This makes these cells the most likely initial infection route for the virus.”

From there, the novel coronavirus can affect the airways and lungs.

The virus - which has spread to more than 184 countries - is thought to be spread via respiratory droplets released when an infected person coughs or sneezes.

The researchers analysed multiple Human Cell Atlas consortium datasets of single cell RNA sequencing from more than 20 different tissues of non-infected people.

Cells from the lung, nasal cavity, eye, gut, heart, kidney and liver were examined, and the researchers studied which individual cells expressed both of two key entry proteins that are used by the virus to infect our cells.

Speaking on behalf of the HCA Lung Biological Network, Dr Martijn Nawijn, from the University Medical Center Groningen in the Netherlands, said: “This is the first time these particular cells in the nose have been associated with Covid-19.

“While there are many factors that contribute to virus transmissibility, our findings are consistent with the rapid infection rates of the virus seen so far.

“The location of these cells on the surface of the inside of the nose make them highly accessible to the virus, and also may assist with transmission to other people.”

The study suggests that ACE2 receptor production in the nose cells is probably switched on at the same time as other immune genes that are activated when cells are damaged or fighting infection.

The researchers also found the key entry proteins ACE2 and TMPRSS2 in cells in the cornea of the eye and in the lining of the intestine.

The virus can spread through coughs and sneezes
The virus can spread through coughs and sneezes

The finding suggests another possible route of infection via the eye and tear ducts - and raises the potential of fecal-oral transmission.

The HCA Lung Biological Network is continuing to analyse the data - available at https://www.covid19cellatlas.org/ - for further insights into the cells and targets likely to be involved in Covid-19 and to relate them to patient characteristics.

Prof Jayaraj Rajagopal, a member of the network and pulmonologist in the Department of Internal Medicine at Massachusetts General Hospital, said: “The cellular basis of disease often does not receive as much attention as the molecular basis of disease, even though molecules and cells are inseparably linked. In the case of Covid-19, knowing the cells that act as portals of viral entry and possible viral reservoirs helps us think about why a virus can be transmitted easily between people and why only some people progress to a lethal pneumonia.

“Most studies of coronaviruses don’t use cells from the actual tissues that are infected in patients.The HCA hopes to point both virologists and physicians toward the right cells and tissues for study.”

All the data from the Human Cell Atlas - involving 1,600 people in 70 countries - is openly available to scientists across the globe.

Professor Sir Jeremy Farrar, director of Wellcome, said: “By pinpointing the exact characteristics of every single cell type, the Human Cell Atlas is helping scientists to diagnose, monitor and treat diseases including Covid-19 in a completely new way. “Researchers around the world are working at an unprecedented pace to deepen our understanding of Covid-19, and this new research is testament to this.

“Collaborating across borders and openly sharing research is crucial to developing effective diagnostics, treatments and vaccines quickly, ensuring no country is left behind.”

Joining the Sanger Institute at Hinxton on this study were researchers from University Medical Centre Groningen, University Cote d’Azur and CNRS, Nice and their collaborators.

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