CDC / Alissa Ecker, MS / Dan_Higgins, MAMS

SARS-CoV-2 infects cells via specific viral entry factors that are more abundant in elderly, men and smokers

These findings offer a molecular explanation for the reported differences in disease severity for COVID-19 patients depending on age, gender and smoking status

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A large-scale new study uncovers which cell types in the human body can be infected by SARS-CoV-2 due to their viral entry factors. The research also suggests that increased gene expression of these viral entry factors in some individuals partially explains the differences of COVID-19 severity reported in relation to age, gender and smoking status.

Reported in Nature Medicine on 2nd March 2021, the study was conducted by researchers from Helmholtz Zentrum München, the Broad Institute of MIT and Harvard, the Wellcome Sanger Institute and University Medical Center Groningen and their collaborators in the Human Cell Atlas Lung Biological Network. This is part of the Human Cell Atlas* effort to map every cell type in the human body, transforming our understanding of biology and disease.

COVID-19 does not affect everyone in the same way. While the coronavirus, SARS-CoV-2, primarily manifests in the lung, it can infect other organs, too. Clinical observations throughout the pandemic also suggest that some population groups – such as elderly people, men and smokers – tend to be more severely affected by the disease. So far, the molecular reasons for this have not been described.

Previous studies had shown that in order to infect human cells, SARS-CoV-2 needs the cell to contain specific genetic viral entry factors – an ACE2 receptor and a TMPRSS2 or CTSL protease. In this study, researchers from the Human Cell Atlas Lung Biological Network joined forces to contribute and analyse gene expression data from individual cells. Together, they analysed more than 100 datasets of single-cell gene expression of healthy people, to see which cell types express both ACE2 and a protease.

The analysis showed that specific cell types in the epithelium of the lung and airways, and also in the liver, the colon, and the eye had high expression of the ACE2 receptor and TMPRSS2 protease genes. This means they could potentially be infected with SARS-CoV-2.

The researchers found that these particular cell types from elderly people had higher expression of these entry factors, and that the cells from men had slightly greater expression than from women. In addition, these cells from smokers, in particular airway cells, express more SARS-CoV-2 entry factors than from non-smokers. These findings match the reported differences in disease severity for COVID-19 patients with age, sex and smoking and offer a molecular explanation for this difference.

“Fighting the pandemic, we cannot rely on conclusions that are limited to only a few observations. Instead, we must rely on robust analysis of big data. For example, to assess whether the ACE2 receptor required for virus entry is more abundant in cells of the elderly population, we need a strong representation of many diverse individuals in our dataset. Using data from the Human Cell Atlas, we could model how genetic viral entry factors in cells are expressed across the population.”

Dr Malte Lücken, computational biologist at Helmholtz Zentrum München and a co-first author of the study

“A key aspect of this large-scale study was the age range of samples we were able to analyse. This study included data from human developmental stages, samples from children and young adults, as well as samples from elderly people. This gave us unique power to assess changes occurring over the human lifetime. The sheer scale of the data allowed us to see molecular differences with age, sex and smoking status.”

Dr Kerstin Meyer, an author on the paper from the Wellcome Sanger Institute

The study investigated which cells are most likely to be infected by SARS-CoV-2. The connection between high expression levels of viral entry factors and increased ease of infection or disease severity has been shown in mice and in the laboratory, but further validation is needed to prove this connection in humans. Other possible factors such as immune system strength were not included in this study.

“This study was the epitome of a whole field coming together. Within the Human Cell Atlas consortium everyone who generated data on the healthy human lung contributed their data, both published and unpublished, to enable our analysis. When we then reached out beyond the consortium, more labs also contributed data to the effort. Only through these contributions was our analysis made possible.”

Professor Fabian Theis, Director of the Institute of Computational Biology at Helmholtz Zentrum München, and Associate Faculty member of the Wellcome Sanger Institute, who coordinated the study

The molecular profile of the cells partially explains how disease severity might differ between population groups, and provides a target for further research. Moving forward, the findings may also help better understand the spread of the coronavirus across the body.

More information

*The Human Cell Atlas (HCA) is an international collaborative consortium which is creating comprehensive reference maps of all human cells—the fundamental units of life—as a basis for understanding human health and for diagnosing, monitoring, and treating disease. The HCA will impact every aspect of biology and medicine, propelling translational discoveries and applications and ultimately leading to a new era of precision medicine. The HCA was co-founded in 2016 by Dr Sarah Teichmann at the Wellcome Sanger Institute (UK) and Dr Aviv Regev, then at the Broad Institute of MIT and Harvard (USA). A truly global initiative, there are now more than 2,000 HCA members, from 75 countries around the world.

The Human Cell Atlas Lung Biological Network is a consortium of more than 70 scientists who collaborate on mapping the airway cells in our body. This group is coordinated by Drs Martijn Nawijn, Pascal Barbry, Alexander Misharin and Jayaraj Rajagopal.

Further HCA research on COVID at:

The data from this research is available at:


Muus/Lücken et al., 2021: Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nature Medicine, DOI: 10.1038/s41591-020-01227-z


This study was supported by many funders including National Institutes of Health, Medical Research Council, the European Research Council, European Commission, HubMap consortium and Stanford Child Health Research Institute, the Chan Zuckerberg Initiative (CZI), Wellcome and many others. Please see the paper for full funding details.