Women’s immune system responds better to COVID-19, study shows

When researchers reanalyzed datasets from more than 1,000 patients, they found differences between men and women in the expression of genes associated with the functioning of immune cells and the production of inflammatory molecules. The findings point to possible targets for treatment of both sexes.

By André Julião | Agência FAPESP – An international group of researchers supported by FAPESP reanalyzed and integrated thousands of datasets relating to the functioning of the immune systems of COVID-19 patients, establishing possible factors to explain the lower incidence of severe cases of the disease among women. The results pave the way for research on potential therapeutic targets to reduce morbidity and mortality induced by the novel coronavirus. A paper describing the study is published on the preprint platform medRxiv while awaiting peer review.

“We found that women respond more appropriately to the virus. Their immune system activates cytokine responses intensely but doesn’t involve as much of certain kinds that could damage organs. At the same time, neutrophil gene expression is reduced in infected women. Neutrophils can damage tissue, and this is critical in COVID-19,” said Otávio Cabral Marques, a researcher at the University of São Paulo’s Institute of Biomedical Sciences (ICB-USP) in Brazil and principal investigator for the study.

FAPESP supported the study, which was associated with three projects, two also led by Marques, and with a postdoctoral fellowship awarded to Paula Paccielli Freire, first author of the paper and also a researcher at ICB-USP.

With the aid of bioinformatics tools, the researchers reanalyzed datasets from the public functional genomics data repository GEO (Gene Expression Omnibus). The data related to global transcriptional profiles based on nasopharyngeal swabs and blood work from over 1,000 individuals with COVID-19. They concluded that the immune systems of women in various age groups have a similar profile to those of young patients, while men more closely resemble older patients, whose response to infection by SARS-CoV-2 is known to be less effective.

Why women are more protected is poorly understood, but part of the explanation may be that several female hormone receptors are expressed in the immune system. Lifestyle could be another factor, including the lower prevalence of smoking and alcohol consumption among women, for example. 

Lifestyle data is not available from the repository in question, however. “The phenomenon may reflect a combination of these hormonal and behavioral factors,” Marques said. “We have no way of knowing with the information available.”

Therapeutic target

The researchers found that several signaling pathways were differently expressed in men and women. These groups of genes could be targets for future treatment strategies. Drugs already known to regulate the pathways in question could be used, for example, to inhibit excessive expression of cytokines, which are released to defend the organism against the virus but in excess can cause potentially fatal damage to organs, and especially the respiratory system.

Inhibition of some of the genes involved in these pathways, such as CXCR2 and IL-1β, has had promising results in autoimmune disease experiments. This kind of treatment could be an alternative to prevent progression to severe forms of the disease in both men and women, regardless of age.

“The findings include information that will be useful for treatment,” Marques said. “Although the study suggests why men are more susceptible to severe COVID-19, these pathways appear to play an important role in progression to the severe form of the disease in any individual. For example, hospitalized patients could be given a drug to inhibit one of these pathways and avoid excessive inflammation before lung damage occurs. This is a hypothesis we want to investigate.”

The article “Specific immune-regulatory transcriptional signatures reveal sex and age differences in SARS-CoV-2 infected patients” can be read at: www.medrxiv.org/content/10.1101/2020.11.12.20230417v1.