Severe courses with SARS-CoV-2:

Viral entry factors are more abundant in elderly, men and smokers

A new study confirms it: the cells of older persons, men and smokers possess increased viral door openers for the coronavirus. This could be an explanation for more severe courses of COVID-19 in these groups. The study originated as part of the Human Cell Atlas Lung Biological Network. Meshal Ansari from the research group "Cell Circuits in Systems Medicine of Lung Disease" of DZL-PI Herbert Schiller was involved.

COVID-19 does not affect everyone in the same way. While 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 – namely an ACE2 receptor and a protease (TMPRSS2 or CTSL). Knowing which cell types express both ACE2 and a protease would therefore give us information about which cells can potentially be infected with SARS-CoV-2.
The Human Cell Atlas (HCA) consortium is aiming to map every cell type in the human body, transforming our understanding of biology and disease. Within this, researchers from the HCA 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, but also in the liver, the colon, and the eye are rich in genetic viral entry factors (=high expression of ACE2 receptor and a protease) – and therefore contain the necessary molecules to allow SARS-CoV-2 infection.  

Moreover, the researchers found that the expression of genes underlying the viral entry factors is increased in the cells of elderly people and slightly in men compared to women. In addition, cells from smokers (in particular airway cells) express more SARS-CoV-2 entry factors than from non-smokers.

These findings match differences in disease severity that have been reported for COVID-19 patients in those population groups and thus offer a molecular explanation for this difference (next to other factors which were not investigated in this study such as a weaker immune system).

Big Data for Biomedical Research

“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,” adds DZL-PI Fabian Theis, Director of the Institute of Computational Biology at Helmholtz Zentrum München.

Strengths and Limitations

The study investigated which cells are most likely to be infected by SARS-CoV-2. The results partially explain how  disease severity might differ between population groups because of the molecular profile of cells. This provides a target for further intervention research. Moving forward, the findings may also help to better understand the spread of the corona virus across the body. The connection between viral entry factor expression and increased ease of infection or disease severity has been shown in mice and in the lab, but requires further validation in humans.

Original Publication:
Muus/Lücken et al., Nature Medicine, 2021: Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics.