"Exciting" study explains why men are more vulnerable to coronavirus

Anyone can get Covid-19, but not everyone suffers the same consequences. For some, it's a disease with no symptoms; for others, it's deadly. Men are consistently more likely to die.

For instance, in Europe, the World Health Organization reports that men make up 58 percent of Covid-19 deaths. Higher rates of death for men have also been reported in China and in the US.

While scientists have known Covid-19 is killing more men than women, why that is hasn't been certain. Now, a new study is pointing scientists in a promising direction, suggesting that men's immune systems may handle the virus differently.

In a paper published Wednesday in Nature, scientists at Yale University led by Akiko Iwasaki report that men they studied with Covid-19 had a less robust T-cell response to the virus than women.

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T-cells are specialized fighters within the immune system's arsenal. Some types of T-cells can destroy cells that have been infected with the virus, while other types help the body produce antibodies that can help stop the virus from infecting a cell.

That lower T-cell response seen in men was linked to future worsening of the disease, the scientists report.

This study is a deep dive into the immune system that illuminates a robust global trend: A July study on 10,962 Covid-19-related deaths helped solidify the idea that men have higher risks of death from Covid-19 compared to women of the same age.

Warner Greene, an immunologist and director of The Gladstone Center for HIV Cure Research, tells Inverse that this new paper is "provocative," "highly interesting," and done by a "super-talented group of investigators." It also hints at why men oftentimes are more at risk.

"I have the sense they are indeed getting at some of the fundamental gender differences that underlie the different responses of men and women to SARS-CoV-2 infection," he says.

Sabra Klein a professor of molecular microbiology and immunology at Johns Hopkins University agrees. She was also not involved with the research but tells Inverse that the research is “exciting” and provides "new clues" into why men's immune systems may lose the fight against Covid-19.

Men, women, and Covid-19– The study was conducted on a relatively small sample for the science world: 17 men and 22 women who were admitted to the hospital after testing positive for Covid-19.

In that cohort, people weren't in the ICU and weren't receiving any steroids to help boost immune response, so the scientists were able to see how their immune systems responded naturally to the virus. The team also included another group of 59 people, some of whom were admitted to the ICU with severe disease, and finally, a control group of non-infected healthcare workers.

Overall, the women with Covid-19 had elevated T-cell responses compared to men and healthy controls (the latter is expected).

Crucially, the study wasn't all good news for women: Some women also had higher levels of two types of cytokines. This is a group of signaling proteins that the immune system uses to communicate. Higher levels of these cytokines were linked to more severe disease progression, even though their T-cell responses weren't different from those with the lesser disease.

The encouraging takeaway — Greene says that this study suggests different men and women might benefit from different treatments.

• In men, we may need to boost T-cell responses, perhaps through a vaccine, to prevent worsening disease.
• In women, we may need to "blunt" certain cytokine responses early on during infection to prevent worsening disease.

Klein cautions that this study can't give us the whole story on sex and Covid-19. It does show that immune reactions may differ between sexes, but there are other biological differences like genetics or sex hormones (like estrogen or testosterone) that weren't measured here. These could also affect how the disease progresses in men and women.

"I think that this study provides exciting clues into the immune responses that differ between men and women who are infected with SARS-CoV-2, but does not tell us the mechanisms underlying why men are twice as likely to die from COVID-19," Klein says.

Because the average age of female study participants was about 60-years-old, the study authors suggest that sex hormones may not be as powerful a factor. This still leaves other avenues untapped.

"I anticipate this work will have high impact... "

For example, it's well-established that age increases risk for Covid-19. The paper suggests we might approach the age question, in relation to gender disparities and coronavirus, with a bit more nuance.

In men, the team found that the older the men got, the worse their T-cell response seemed to be. However, that wasn't the case for women. As Iwasaki told The New York Times, women as old as 90 "are still making pretty good, decent immune response."

The fact that women tend to have strong immune responses isn't exactly new. A 2018 PNAS paper found that female mice had stronger immune responses when given flu vaccines. Women's immune systems also tend to fare better against HIV once they're infected, a 2007 study on 2,620 patients found.

However, that strong response is not always a good thing: more women suffer from autoimmune diseases (where an overactive immune system attacks the body) than men do.

When it comes to Covid-19 the fact that women tend to carry on a robust T-cell response may prove to be helpful, especially if those cytokines that appear to make the disease worse can be managed. Those cell responses also offer a trail scientists could follow as they try to boost immunity in men. Klein says that this is a key finding:

"The more robust T cell responses in older women could be an important clue to protection and must be explored further," she says.

Greene's intuition says that this paper will spark many more like. Those may give us better answers.

"I anticipate this work will have high impact and will galvanize a large number of follow-up studies," he adds.

Abstract: A growing body of evidence indicates sex differences in the clinical outcomes of coronavirus disease 2019 (COVID-19)^1–5. However, whether immune responses against SARS-CoV-2 differ between sexes, and whether such differences explain male susceptibility to COVID-19, is currently unknown. In this study, we examined sex differences in viral loads, SARS-CoV-2-specific antibody titers, plasma cytokines, as well as blood cell phenotyping in COVID-19 patients. By focusing our analysis on patients with moderate disease who had not received immunomodulatory medications, our results revealed that male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. In contrast, female patients mounted significantly more robust T cell activation than male patients during SARS-CoV-2 infection, which was sustained in old age. Importantly, we found that a poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients. Conversely, higher innate immune cytokines in female patients associated with worse disease progression, but not in male patients. These findings reveal a possible explanation underlying observed sex biases in COVID-19, and provide an important basis for the development of a sex-based approach to the treatment and care of men and women with COVID-19.