ACE2 protein may help explain sex differences in COVID-19 outcomes

Researchers at the University of Toronto’s Emerging and Pandemic Infections Consortium (EPIC) has unveiled the biological factors behind the differing COVID-19 outcomes between males and females. While this pre-clinical research has yet to be confirmed in humans, it highlights the role of the ACE2 protein in contributing to these disparities.

Early in the pandemic, medical professionals observed that males were more susceptible to severe COVID-19 outcomes, such as hospitalization and death, despite similar infection rates across genders and age groups worldwide.

The study, led by senior author Haibo Zhang, a staff scientist at St. Michael’s Hospital, Unity Health Toronto, and a professor at U of T’s Temerty Faculty of Medicine, was a collaborative effort involving EPIC and its five hospital research partners.

The ACE2 protein, found on cell surfaces, plays a crucial role in regulating blood pressure, inflammation, and organ protection during infections like SARS-CoV-2. The gene for ACE2 is located on the X chromosome, meaning females have two copies while males have one.

In healthy individuals, the additional ACE2 gene copy in females doesn’t seem to make a difference. However, following a SARS-CoV-2 infection, males experienced a significant drop in ACE2 levels, while females maintained consistent levels. This suggests that the extra ACE2 gene copy on the X chromosome helps females maintain higher ACE2 protein levels, which could be protective.

Changes in ACE2 levels also correlated with reduced estrogen signaling in males, potentially contributing to the gender-specific differences in COVID-19 outcomes.

To test whether low ACE2 levels were responsible for severe outcomes in males, the researchers used an inhaler to deliver lab-made ACE2 proteins directly into the lungs of infected males. This approach reduced virus levels in their lungs, decreased lung damage, and increased estrogen signaling.

These findings clarify how the extra ACE2 gene copy and higher estrogen levels in females work together to protect them from severe COVID-19 outcomes. Instead of increasing infection rates, the enhanced ACE2 activation in females appears to serve as a compensatory mechanism safeguarding vital organs.

The inhaled ACE2 could serve as a protective measure for individuals entering high-risk situations or as a treatment to reduce hospitalization and mortality after infection.

The potential implications of this research are promising, offering a faster and more effective strategy for preventing and treating COVID-19 in humans. This innovative approach could be a game-changer for protecting lung health in high-risk situations and post-infection recovery.

Source: University of Toronto

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