In the ongoing 2019-nCoV epidemic across China, the deaths have been skewed two to one in favor of men. A new study, if confirmed by later research, may begin shining some light onto why this is happening.
A recent Chinese analysis of a single cell RNA-seq dataset suggests that men and Asian people may have higher expression of ACE2, the cell surface protein that 2019-nCoV uses to attack humans cells, on the alveolar epithelial cells inside the lungs that ACE2 usually infects.
The authors posit that this may be the source of the virus’s observed tendency to be more severe in men, and that the virus may be more severe in Asian people of both sexes for the same reason. The study is based on a tiny sample and is far from conclusive, but the hypothesis is intriguing and has some contextual support from data on influenza and SARS.
Gene expression studies measure the expression of genes in different cell types of the body under different conditions. All human genes are present as DNA in the nucleus of every nucleated cell in the human body, but they must be transcribed into messenger RNA (mRNA) and then translated into proteins by ribosomes in order to function within the cell. mRNA-seq studies sequence the mRNA in a biosample the same way a genome is sequenced, but instead of telling what’s in the genome, they tell which genes are turned on and how much. The single cell mRNA-seq technique separately sequences the mRNA of a number of individual cells.
This study analyzes the distribution of ACE2, a cell surface enzyme that converts angiotensin to regulate blood pressure, and which is also the attack point for both influenza, SARS, and 2019-nCoV. In theory, higher expression of ACE2 on cells in the lungs may make them more susceptible to attack by 2019-nCoV.
The study’s details
The current study comes from a group of scientists at universities in China, re-analyzing a single cell mRNA-seq dataset of lung tissue cells from an earlier study at Northwestern University. The analysis separated the cells into different types based on their transcriptional profile, and found that within the tissues of the alveolae, the small lung structures that play host to the diffusion of gases between the air and blood, expression of ACE2 is concentrated on a rare subtype of cells called AT2 cells, or Alveolar, type two, cells.
They looked at the differential frequency of these cells in the alveolar tissue of the eight donors, and found that expression was higher among the two men than the six women. Only one donor was an Asian man, but his expression of ACE2 on AT2 cells was significantly higher than all the other samples in the study.
Astute readers will have already noticed a key limitation in this study: tiny, tiny numbers. It’s not really possible to conclude from these results on only two men, only one of them Asian, that men have higher ACE2 expression in lung AT2 cells than women or that Asian people have higher expression than white and black people. The results can only be treated as suggestive, and in the eyes of skeptics, not even that.
Unfortunately, generating more data of this type will be difficult, as it requires a lung tissue sample. And in any event, single cell mRNA-seq is notoriously expensive. Some alternate methods might help to investigate this question, like fluorescent study of ACE2 expression on lung cells, and genetic analysis to see if expression QTL hits for higher ACE2 expression in primary lung tissue are enriched among particular populations. These avenues among others may be explored if other scientists find the results in this report worth following up on.
One possible objection to the report is that if it is true, and if higher ACE2 expression is a mechanism by which 2019-nCoV attacks men more fiercely than women, then we should expect to see the same effect with other viruses attacking ACE2, like SARS and influenza.
However, there is some data suggesting this may in fact be true of the other two diseases. The 1918 pandemic flu had a higher CFR among men than women, and so did the SARS epidemic.
Average symptom severity and duration of infection of the seasonal flu are also higher among men than women.
A quick search revealed that some flu severity risk variants appear more commonly in Asian people than white people, but no data on whether Asian people experience the seasonal flu more severely.
This line of inquiry is interesting, but it’s unclear what significance it may have, e.g. whether attempting to reduce ACE2 expression in AT2 cells, cleave it from the cell surface, or blockade it, may be an effective strategy against 2019-nCoV. ACE2 is already a known drug target for some blood pressure medicines, although by an enzymatic inhibition mechanism, not a receptor blockade mechanism. Most likely, these results, even if confirmed, will be nothing but intriguing trivia.
