Covid: early production of IFN alpha, an advantage in women that persists with age

Covid: early production of IFN alpha, an advantage in women that persists with age

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Why do women defend themselves better against Sars-CoV-2? Several pathways have been proposed to explain the female immune advantage. Inserm/CNRS/University of Toulouse III – Paul Sabatier/Researchers from the University Hospital of Toulouse show that the production of interferon alpha, previously in women, could be protective.

The results published in “eBioMedicine” reveal that these specificities are maintained with advancing age and are based on a specific type of cells involved, the plasmacytoid dendritic cells.

Against viruses such as the flu, HIV or even Sars-CoV-2, women tend to develop more effective immunity than men. Research suggests a role for hormones (estrogens) and sex chromosomes in these differences. “In fact, a large part of the immunity genes are found on the X sex chromosome, which is present in two copies in women, compared to only one in men”explained in a press release from Inserm.

Toll-7-like receptor

If the expression of genes present on the second X chromosome is mainly repressed, between 15 and 23% of these genes remain active. This is the case of the gene that encodes the so-called “Toll-7-like” cell receptor, which is expressed more strongly in women. This receptor, located on plasmacytoid dendritic cells, recognizes viral RNA and triggers an immune response via the secretion of interferon type 1 (IFN 1), these antiviral and immunoregulatory molecules. The rapid production of IFN 1 in the respiratory tract during infection protects against severe forms; the lack of expression of this protein would explain a quarter of the severe cases.

“The immune response linked to the Toll-7 receptor is a first line of defense against RNA viruses”, is recalled in the press release. The ability of plasmacytoid dendritic cells to produce higher amounts of IFN 1 is one of the reasons for the better resistance of women. The research team from the Toulouse Institute of Infectious Diseases led by Jean-Claude Guéry in collaboration with Pr Antoine Blancher from Toulouse University Hospital sought to characterize the production of IFN alpha, a subcategory of IFN 1 , and the effect of sex and years .

For their study, the researchers measured IFN alpha production in a cohort of 310 women and men aged 19 to 97 years. To do this, they used substances capable of activating various innate immunity receptors, such as the Toll-7 and Sting receptors present on the surface of various immune cells.

Of the seven types of inflammatory molecules studied, IFN alpha was the only one that showed a sex-related difference in production: the level remained significantly higher in women after Toll-7 receptor stimulation. And despite the very marked decline in plasmacytoid dendritic cells with age in women, the finding remained the same: IFN alpha secretion was always much higher in the participants, even those over 80 years of age.

Key role of X-linked genetic factors

Other observations: the production of IFN alpha linked to the stimulation of the Sting receptor correlates with monocytes, whose number increases after 60 years of age, especially in men. “These results show for the first time that monocytes are the main source of IFN alpha production in the blood, via activation of the Sting receptor, suspected of being the cause of the deleterious late production of type 1 interferons in Covid-19 infection”, stresses Jean-Claude Géry. However, IFN 1 is clearly beneficial during the early phase of infection, such as those produced by plasmacytoid dendritic cells via Toll-7 activation »he continues.

This work thus opens up new avenues in the search for immunity genes present on the X chromosome and susceptible to being overexpressed in women. For the researcher, “The fact that the difference in IFN alpha production between the sexes persists with age and remains greater in women after menopause cannot be explained by an effect of sex hormones and suggests a key role for genetic factors. related to the X chromosome..

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