Covid-19: the immune differences between men and women deciphered

Researchers from Inserm, CNRS, Toulouse III – Paul Sabatier University and Toulouse University Hospital have looked into the cellular origin of IFN-α production and the reasons for its higher production. in women than in men. Their results published in eBioMedicine show that this immune advantage is maintained with advancing age and define two specific types of immune cells involved: plasmacytoid dendritic cells and monocytes.

The performance of the immune response to a viral infection differs according to biological sex: when faced with viruses such as fluthe HIV or even the SARS-CoV-2 responsible for Covid-19women often develop better immunity than that of men. Recent research suggests an involvement of hormone (estrogen) and sex chromosomes in these differences.

The X sex chromosome carries immunity genes

Indeed, a large part of the immunity genes are located on the X sex chromosome, which is present in two copies in women, against only one in men.

The expression of the genes present on the second X chromosome is mainly repressed, but between 15 and 23% of these genes remain active. This is particularly the case for the gene coding for the so-called “Toll-7 type” cellular receptor, which is consequently more strongly expressed in women than in men. Present in immune cells called “plasmacytoid dendritic cells”, this receptor allows them to recognize the RNA of viruses and trigger an immune reaction. via the secretion anti-viral and immunoregulatory molecules: type I interferons. The immune response linked to the Toll-7 receptor is an essential line of defense against RNA viruses, such as SARS-CoV-2; the rapid production of type I interferon in the airways during infection protects against severe forms of Covid-19.

The role of type I interferons

The ability of women’s plasmacytoid dendritic cells to produce greater amounts of type I interferons is believed to be one of the reasons why they exhibit better resistance to Covid-19 than men. However, until now, researchers did not know whether this “immune advantage” persisted in very old women.

A research team from the Toulouse Institute of Infectious Diseases (Inserm/CNRS/Toulouse III University – Paul Sabatier) led by Jean-Charles Guéry, Inserm Research Director, in collaboration with the team of Professor Antoine Blancher from the Toulouse University Hospital , studied the effect of sex and age on the production of interferon alpha (IFN-α), a subcategory of type I interferons, and sought to identify the cells responsible for this production.

Lasting protection for seniors

In cohort of 310 women and men aged 19 to 97 in apparent good health, the researchers measured the production of IFN-α after stimulation by substances capable of activating various receptors ofimmunity innate, such as Toll-7 and STING receptors, expressed by different immune cells in the blood.

They observed that only plasmacytoid dendritic cells produced IFN-α after specific stimulation of the Toll-7 receptor. Out of 7 types of inflammatory molecules studied, IFN-α was the only one to show a sex-related difference in production: during stimulation of the Toll-7 receptor, its production remained significantly greater in women. Even though the number of plasmacytoid dendritic cells decreases with age and much more markedly in women, the secretion of IFN-α remained very much higher in the participants, even in the oldest of them. (over 80 years old).

Conversely, the production of IFN-α linked to stimulation of the STING receptor did not appear to be correlated with gender, age, or the number of plasmacytoid dendritic cells. The study reveals that this production is correlated with the abundance of other immune cells: monocytes, whose number in the blood increases after the age of 60, particularly in men.

Women more armed against Covid than men

According to Jean-Charles Guéry, “ these results show for the first time that monocytes are the preeminent source of IFN-α production in the blood, via the activation of the STING receptor, suspected to be at the origin of the late harmful production of interferons type I in Covid-19 infection “. However, type I interferons are on the other hand clearly beneficial when they intervene during the early phase of the infection, “ such as those produced by plasmacytoid dendritic cells via Toll-7 activation “, specifies the researcher.

These observations suggest that the production of IFN-α, via stimulation of the Toll-7 receptor, would contribute, including in elderly women, to strengthening resistance against SARS-CoV-2 and other viral infections. ” However, the fact that the difference in IFN-α production between the sexes persists with age and remains greater in women well beyond menopausecannot be explained by an effect of sex hormonesand suggests a key role for factors genetic linked to the X chromosome adds Jean-Charles Guéry.

This work thus opens the way to new avenues in the search for immunity genes present on the X chromosome and likely to be overexpressed in women.

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