In recent weeks we have heard that the SARS-CoV-2 coronavirus affects men more than women. The explanations given usually point to biological differences, although sometimes with some confusion. Let’s try to clarify the matter.
Humans have 23 pairs of chromosomes in each of our cells. 22 of them condense –packaging– during cell division. The other pair, which determines sex, is XX when it corresponds to women and XY when it is to men.
Chromosomes become fully or partially decondensed after division, since a condensed chromosome cannot be copied to RNA and express proteins. That is, it is inactive.
The presence of two Xs in women intrigued researchers for a long time, since for that chromosome they would have twice as many genes as men, something that is usually a problem at a biological level. There had to be some compensation mechanism so that the amount of genes expressed by the two sexes was the same.
Everything seemed to clear up with the discovery of a dense structure in the nucleus of cells that are not dividing. This, called Barr’s corpuscle , was one of the female X chromosomes, apparently condensed for life.
What does this have to do with the coronavirus?
One of the mechanisms that SARS-CoV-2 uses to enter our cells consists of the interaction with the ACE2 protein. Guess where the gene that codes for it is? Indeed, on the X chromosome.
A question then arises: if men and women have the same amount of ACE2, why are infections in men more numerous? It has been reported that women have twice the amount of ACE2 because they have two X chromosomes. But haven’t we said they don’t? It is also affirmed that ACE2 has an anti-inflammatory effect, so that women would be protected while men, especially the elderly, with less receptor, would have more risk: even if they infected less, they would not be as well protected.
Too much seemingly contradictory message.
For starters, the decline in ACE2 with age is something that has only been proven in rats. Let us imagine, however, that it is so. It is clear from recent experience that older people are more severely infected. The most plausible explanation would be that binding of the virus to the receptor would inhibit the usual anti-inflammatory and vasodilator function that ACE2 has.
The balance between the ACE2 and ACE (pro-inflammatory) proteins would be broken in favor of the latter as the former is occupied, linked to the coronavirus. This disruption of the balance in favor of inflammation, which would occur in both the elderly and the young, would be especially harmful for the elderly and people with previous pathologies.
But what about the higher incidence in men? It soon became clear that, contrary to expectations, not all of the X chromosome remains silenced. Of the more than 600 genes it contains, just over half are never expressed. Surprisingly, the rest do, regularly or sporadically.
The important thing in this story is that the ACE2 receptor is one of those that is always expressed and, in addition, it does so together with some genes related to immune defense. Indeed, the X chromosome contains more genes related to our immune system than any other.
This is an advantage for individuals with two X chromosomes, although it also has a negative side: women are more prone to autoimmune diseases, those in which we attack our own cells, than men.
A mystery yet to be solved
There is not yet a definitive answer to explain why men suffer more from COVID-19, but we can point to several causes. The first is that ACE2 may not be the only protein with receptor function in the virus.
The second, that it is not true that men have fewer receptors. They have fewer copies of the gene, but there are male tissues where more ACE2 protein is expressed than in women. It is one thing to have a gene and another to express it. One of the regulatory elements of it are hormones. Indeed, it has been discovered that the expression of ACE2 depends more on the absence of estradiol than on the number of X chromosomes. Thus, it has been found in mice that males are more likely to be infected than females, but these possibilities are equalized by inhibiting estrogens from these, which has led to clinical trials being conducted supplying estrogens to men.
And what about postmenopausal women? They also suffer less from the virus than men their age, yet their hormone levels are low. The explanation here would lie in the expression of its more numerous genes related to immune defense.
In short, without forgetting other aspects such as healthier lifestyles, everything indicates that hormones and a higher number of active genes linked to the X chromosome provide women with greater protection and response capacity against this and other pathologies.
Jose Antonio Uranga is a professor of Cell Biology and Histology at the Rey Juan Carlos University.
This article was originally published on The Conversation. Read the original.
