Scientists are creating a map of the human body to identify locations where the COVID-19 virus can enter human cells.

The research, from a number of international institutions including Imperial College London, has so far identified likely initial infection points for SARS-CoV-2 (the virus causing COVID-19) in the nose and eyes. Receptors were also found in the intestines and in vital organs such as the heart.

Heart tissue damage and consequent heart failure is observed in up to 20 per cent of COVID-19 patients. Dr Michela Noseda Study author

The findings, published in the journal Nature Medicine, highlight two specific cell types in the nose – called goblet and ciliated cells, as likely initial infection points for COVID-19.

Scientists found these cells have high levels of the entry proteins that the COVID-19 virus uses to get into our cells.

The team, which includes researchers from the Wellcome Sanger Institute, University Medical Centre Groningen, University Cote d’Azur and CNRS, Nice, say the findings could help explain the high transmission rate of COVID-19.

The SARS-CoV-2 coronavirus requires two key proteins, called ACE2 and TMPRSS2, to enter human cells. The first is a receptor protein that the virus can dock to, while the second is a so-called protease that activates viral entry into the cell.

Scientists across the world are trying to understand exactly how the COVID-19 virus spreads, to help prevent transmission and develop a vaccine as well as understanding the mechanisms that lead to a devastating systemic disease in some patients.

Heart damage in COVID-19 patients

While it is known that SARS-CoV-2 uses a similar mechanism to infect our cells as a related coronavirus that caused the 2003 SARS epidemic, the exact cell types of entry and the target cells that can be reached by the virus after the initial infection had not previously been pinpointed.

In the current paper, scientists analysed genomic data from more than 20 different tissues of non-infected people. The researchers looked for which individual cells expressed both of two key entry proteins that are used by the COVID-19 virus to infect our cells.

Dr Michela Noseda, a senior study author from the National Heart and Lung Institute at Imperial, explained the study has revealed crucial insights - not only into how the virus gains access to the body, but also how the virus could target organs outside of the airways and leading to a systemic disease: “Heart tissue damage and consequent heart failure is observed in up to 20 per cent of COVID-19 patients. Thus, it was crucial to investigate how the virus could enter heart cells, by mapping the location of the SARS-CoV-2 receptor in the heart, and the proteases that enable the virus to gain entry to cells.

Coronavirus

"We analysed around 500,000 single cells from 14 human hearts and identified three types of cells that express the entry receptor: pericytes, which are found in the network of small blood vessels in the heart; cardiac muscle cells; and fibroblasts, the cells that help maintain the heart structure. Knowing the specific and likely target cells of the virus in the heart provides crucial information necessary to understand the mechanisms of damage, and guide treatment choices.”

Virus enters the tear ducts

To discover which cells could be involved in COVID-19 transmission, researchers analysed data from the Human Cell Atlas consortium. This project aims to create reference maps of all human cells to understand health and disease. More than 1,600 people across 70 countries are involved in the HCA community, and the data is openly available to scientists worldwide.

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.”

The two key entry proteins ACE2 and TMPRSS2 were also found in cells in the cornea of the eye and in the lining of the intestine. This suggests another possible route of infection via the eye and tear ducts, and revealed a potential for fecal-oral transmission.

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. Professor Sir Jeremy Farrar Director of Wellcome

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 global HCA Lung Biological Network continues to analyse the data in order to provide further insights into the cells and targets likely to be involved in COVID-19, and to relate them to patient characteristics.

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.”

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Adapted from a press release by the Wellcome Sanger Institute

'SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes' is published in Nature Medicine