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Researchers at Yale University School of Medicine have emphasized the importance of ensuring that studies of patients with coronavirus infection 2019 (COVID-19) report data in a gender-neutral manner.
Gender differences affect the incidence and outcomes of disease in COVID-19, with males at significantly higher risk of death (after age 30) than females.
Because aging is strongly associated with an increased risk of mortality across all sexes, older males are the most prone group to serious disease. The male bias in COVID-19-related mortality has been observed across almost all countries where gender-disaggregated data are available. These data show that the risk of mortality among males is about 1.7 times higher than among females.
Reporting COVID-19 data in a gender-neutral manner is therefore crucial for establishing the pathogenesis of different diseases, promoting understanding of the disease and developing improved prevention and treatment methods, say the researchers. research.
Tools that may underlie the bias
In a scene recently published in the magazine Science, researchers Takehiro Takahashi and Akiko Iwasaki describe some of the biological mechanisms that may underlie male bias toward COVID-19 side effects.
Studies have shown that men often put up weaker immune responses and are more prone to infections than women. They have also shown that the immune response to vaccines is generally stronger in women, although this may lead to immunopathology in cases of infection.
After infection with a virus, the body launches two lines of defense: antiviral responses mediated by type 1 and type 3 interferons (IFNs) to limit viral reproduction and production of cytokines to immune cells such as macrophages and neutrophils depleting infectious cells.
Importantly, COVID-19 is characterized by a strong sex cytokine response and an inexplicably low IFN-mediated response.
In the early phase of COVID-19, males produce higher levels of key immune cytokines than females, while females produce higher levels of type 1 interferon IFNα. Interestingly, in a study conducted last year (2020), autoantibodies against type 1 IFN symptoms were detected in a group of patients with severe disease, 94% of whom were older men.
Another study in 2020, at the early stage of COVID-19, found that T cell activity was strong in older women, but declined in older men. In addition, poor T cell response among men was associated with more severe disease outcomes.
Tools that may underlie the gender differences
The authors argue that the sex chromosomes may be part of a single mechanism that may underlie these gender differences. Many important immunity-related genes are found on the X chromosome and although one copy is in silent or inactive women, some of these genes escape this inactivity. An example is a gene encoding a Toll-like receptor 7, which induces strong IFN type I production in plasmacytoid dendritic cells (pDCs).
Increased expression of these genes in women leads to a stronger type I IFN response than seen in men.
There is another method that may include the different effects of age on immune cell transcripts. Aging causes a more rapid decline in the level of naïve T cells in men than in women, and the rate of B cells decreases only in men older than 65 years.
“Males undergo major and dramatic changes in the epigenetic landscape of their immune cells between the ages of 62 and 64, after which males exhibit an accelerated immunosenescence phenotype,” the researchers wrote.
On the other hand, large changes in the epigenetic landscape of immune cells do not affect women until 5 or 6 years later, with this gap largely in line with the difference in life between both species.
Sex hormones can also play a role
As the first stage of the infection process, SARS-CoV-2 binds to the human host cell receptor angiotensin-converting enzyme 2 (ACE2). Studies of various cell lines and animal models have shown that ACE2 expression is modulated by the sex hormone estrogen, which is produced at a higher density in women than in men.
“Estrogen is a critical regulator of gene expression and activity in immune-mediated immune cells, including monocytes, macrophages, and dendritic cells, as well as in lymphocytes such as T 1/2 helper cells (TH1 / 2 ), regulatory T cells (Tregs), and B cells, ”the researchers wrote.
In addition, levels of one of the major forms of estrogen, called estradiol, and a signal of ovarian reserve called anti-Müllerian hormone are remarkably linked to COVID-19 intensity, contributing to the team.
Data on COVID-19 patients should be disaggregated by gender
Takahashi and Iwasaki warn that data on patients with COVID-19 should be reported in a gender-neutral manner.
The researchers say this would help “not only to explain the pathogenesis of different diseases but also to enable a deeper understanding of this disease and ultimately develop better treatment and prevention strategies. . ”
“It should be standard practice to collect and report non-segregated sex data for this and for all future infectious disease and vaccine studies,” the team concluded.