Scientists are racing to understand exactly how SARS-CoV-2 spreads, to help prevent transmission and develop a vaccine. While it is known that SARS-CoV-2 uses a similar mechanism to infect human cells as SARS-CoV—the cause of the 2003 SARS epidemic—the exact cell types involved in the nose had not previously been pinpointed.

Now, a collaborative group of researchers from the Wellcome Sanger Institute, University Medical Centre Groningen, and the University Cote d’Azur and CNRS, Nice, have identified two specific cell types in the nose as the likely entry points for the virus.

The work is reported in Nature Medicine, in a paper titled “SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes.” This is the first publication with the Lung Biological Network, part of an ongoing international effort to use Human Cell Atlas data to understand infection and disease.

Previous research had shown that nasal swabs from patients with symptomatic or asymptomatic COVID-19 exhibit higher viral concentrations than those in throat swabs, implicating the nasal passage as a potential gateway for initial infection and transmission.

The current study showed that goblet and ciliated cells in the nose have high levels of the entry proteins that SARS-CoV-2 uses to get into our cells. It further shows that cells in the eye and some other organs also contain the viral-entry proteins. The study also predicts how a key entry protein is regulated with other immune system genes and reveals potential targets for the development of treatments to reduce transmission.

To discover which cells could be involved in SARS-CoV-2 entry, researchers surveyed expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. They analyzed multiple Human Cell Atlas (HCA) consortium datasets of single cell RNA sequencing, from more than 20 different tissues of non-infected people. These included cells from the lung, nasal cavity, eye, gut, heart, kidney, and liver.

ACE2 and TMPRSS2 are two molecules involved in SARS-CoV-2 viral entry. 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.

The authors write that they “co-detected these transcripts in specific respiratory, corneal, and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread, and clearance.”

They confirmed the expression of ACE2 in multiple tissues implicated in prior research. They also detected ACE2 expression in tissues not previously analyzed, along with its co-expression with TMPRSS2. The authors found high expression of ACE2 and TMPRSS2 in nasal goblet and ciliated cells, which produce mucus. This suggests that these cells are the location of original viral infection and are possibly the source of dissemination within and between people.

“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,” said Waradon Sungnak, PhD, the first author on the paper and a post-doc in the Teichmann lab at Wellcome Trust Sanger Institute. “We then revealed that mucus-producing goblet cells and ciliated cells in the nose had the highest levels of both these SARS-CoV-2 proteins, of all cells in the airways. This makes these cells the most likely initial infection route for the virus.”

“This is the first time these particular cells in the nose have been associated with COVID-19,” said Martijn Nawijn, PhD, associate professor at the University Medical Center Groningen in the Netherlands. “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 makes them highly accessible to the virus, and also may assist with transmission to other people.”

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 also revealed a potential for fecal-oral transmission.

When cells are damaged or fighting an infection, various immune genes are activated. The study showed that ACE2 receptor production in the nose cells is probably switched on at the same time as these other immune genes.

The work was carried out as part of the global Human Cell Atlas consortium which 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.

Sarah Teichmann, PhD, group leader at the Wellcome Trust Sanger Institute and a senior author on the paper 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 analyze 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.”

The study, noted the authors, “offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients.” For more details, the authors provided their data in a comprehensive, open, and user-friendly fashion at www.covid19cellatlas.org.

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