Sex differences in immune responses to COVID-19

Image credit: Kruthika Sundaram

There are a broad range of COVID-19 symptoms, which widely differ in severity between patients. Age quickly emerged as the most significant predictor of this. COVID-19 related deaths are extremely uncommon in those under 50, but for those over 75, the odds of surviving COVID-19 decreases dramatically. Sadly, over 10 percent of this age group die following infection. Similarly, sex has now emerged as a predictor. Men are nearly twice as likely to die of COVID-19 than women, and 60% of COVID-19 deaths recorded globally are in men.

This trend is not unique to COVID-19. Medical records suggest that men are disproportionately susceptible to viral infection. Women consistently mount a more robust immune response to vaccines than men by generating higher levels of detectable antibodies, and viral infections such as hepatitis A are more prevalent in men than women. Not only are men more likely to contract a viral infection, but the level of infection is also likely to be higher. Male hepatitis C and HIV patients consistently display higher levels of detectable virus when compared to female counterparts.

Since male and female immune systems vary in their response to infection, and since older immune systems are under pressure from age-related inflammation, these observations both point towards the role of an individual’s immune response in determining COVID-19 severity. In fact, exacerbated immune responses tend to be associated with worse outcomes for COVID-19 patients.

A study, recently released pre-print in Nature, aimed to determine if male and female immune systems do indeed respond differently to SARS-CoV-2 infection. Researchers compared the immune response of male and female COVID-19 patients to a control group of health care workers. The immune responses of each person was characterized by measuring the extent of SARS-CoV-2 infection by RT-PCR, and by measuring the abundance and proportions of immune factors, including anti-SARS-CoV-2 antibodies, in blood samples.

Image credit: Kruthika Sundaram

These measurements revealed contrasting immune capabilities between men and women in the early stages of SARS-CoV-2 infection. In the early phase of infection, innate immunity is elevated in males whereas components of the adaptive immune system are increased in females. 

The innate immune system consists of nonspecific responses to infection. This includes inflammation, which is controlled by monocytes and the pro-inflammatory cytokines they produce, both of which are elevated in male patients. In contrast, the adaptive immune system is specific in its action against an infection, aiming to kill the pathogenic cells. It is largely mediated by CD8+ T cells, which are elevated in female COVID-19 patients in the early stages of infection. Interestingly, an elevated innate immune response in female patients was associated with more severe COVID-19 symptoms.

These findings suggest that the heightened innate immune response, and lesser T cell response, to SARS-CoV-2 in men may contribute to their greater risk of fatality compared to women. Therefore, therapies that elevate T cell response may improve outcomes for male patients, whereas suppressors of innate immune activation during early stages of infection may benefit female patients.

Written by Seán Dunphy and edited by Ailie McWhinnie.

Seán’s thoughts… It is rare that two individuals react identically to any infectious disease. Likewise, people rarely react to treatment in the same way. COVID-19 is no different and the emerging evidence for the differences between how men and women react to COVID-19 and its potential treatments are worth noting. These differences, and how strongly they contrast, highlight the need for a personal approach to treating COVID-19. The fact that the difference between the reactions of male and female patients may justify opposing treatments, highlights the danger in treating all COVID-19 patients in the same way. Although the scale of the pandemic places urgency on the need for a treatment, this urgency cannot exceed the danger of treatments which have not been tested with rigour.

Seán is a 3rd year PhD student at the Institute of Cell Biology. Find him on Twitter @SeanJDunphy and LinkedIn @Seán Dunphy.

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