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Sex differences in SARS-CoV-2 immune response

A recent study, published in Nature, has provided evidence that may explain the underlying sex biases that are observed in SARS-CoV-2 disease outcomes.

Sex differences

A growing body of evidence has shown sex differences impact clinical outcomes of SARS-CoV-2. Researchers have found that males are at greater risk of more severe disease, including death. It has been reported that ~60% of deaths from COVID-19 are men.

Previous work has demonstrated that sex has a significant impact on the outcome of other infections such as hepatitis A and tuberculosis. In these infections, researchers have found that the prevalence is higher in men. Male patients also have higher viral loads in hepatitis C virus and HIV. Contrastingly, women mount a robust immune response to vaccinations. Collectively, these findings suggest that women have a more robust ability to control infectious agents.

Nevertheless, our understanding of the mechanisms by which SARS-CoV-2 causes more severe infection in male patients than females is unclear. To investigate this, researchers performed a detailed analysis on sex differences in immune phenotype. They did this by assessing viral loads, SARS-CoV-2 specific antibody titres, plasma cytokines/chemokines and blood cell phenotypes. The analysis focused on 98 patients with moderate disease who had not received immunomodulatory medications.

Immune responses

The researchers found that the levels of several important proinflammatory innate immune chemokines and cytokines such as IL-1, IL-I8 and CCL5 were higher in male patients. The team also observed a more robust T cell response among female patients than males at baseline. In particular, activated CD8 T cells were significantly elevated in female patients but not in male patients, in comparison with healthy controls. Interestingly, they found that T cell response was negatively correlated with patients’ ages in male but not female patients. They found that females’ higher innate immune cytokine levels associated with worsening disease.

These results indicate key differences in the baseline immune capabilities between men and women during the early stages of SARS-CoV-2 infection. They also suggest a potential distinct underlying immunological mechanism of disease progression between sexes. The team believe that experts should take these results into consideration during the prognosis, prevention and treatment of COVID-19 patients. They also suggest that vaccines and therapies that elevate T cell immune response may be beneficial for male patients. However, therapies that dampen the innate immune response would be more advantageous for females.

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