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With more men than women developingsevere illness and dying from COVID-19, sex differences that influence theimmune system may offer answers.

The bias in COVID-19 deaths appearedin the first reports out of China and has also been revealed in countries thatbreak down their mortality data by sex. Of Italys 21,551 deaths recorded as ofApril 20, 64 percent were men. In Spain, 59 percent of the 12,634 deaths as of April 21 occurred in men. Germany had recorded 4,598deaths by April 21, with 58 percent in men.

The United States does notseparate out national COVID-19 mortality by sex, but some states do. New York hasthe highest number COVID-19 deaths in the country, and as of April 21, 60 percent of 15,302 deaths were in men.

Some of that discrepancycould be because men are more likely than women to have other health problems,such as hypertension and diabetes. These are among the underlying conditionsthat raise the risk for severe COVID-19 disease, the U.S. Centers for Disease Control and Preventionreported April 3.

Another possible culprit isthe immune system itself. The many proteins that work together to defend thebody against viruses do not operate exactly the same way in males and females. Thosebiological differences, driven by sex hormones and genes, may be guarding somewomen from the deadliest complications of COVID-19.

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In general, females mount astronger immune response than males, studies have found. This makes womenoverall less susceptible to viral infections than men, although how each individualfares is another matter. A stronger immune response also means females are morelikely to develop autoimmune diseases, when the immune system attacks ones owntissue; conversely, a toned down immune response makes males more prone tohaving a host of malignant cancers.

The sources of the stronger femaleimmune response can be found in both the innate and adaptive immune systems,says Sabra Klein, a virologist at the Johns Hopkins University Bloomberg Schoolof Public Health. The innate system provides the first response against a virus,while the adaptive systems contribution is slightly delayed by the time neededto ramp up antibody production against a new intruder.

One component of the innateimmune system is called toll-like receptor 7. This protein can recognizemolecules found on viruses, thereby outing the pathogens as foreign. The genefor toll-like receptor 7 resides on the X chromosome. Because females have twocopies of the X, the body silences one (SN: 4/8/03),allowing for the right dose of X chromosome genes. But some genes escape the shutdown, and there is evidence that this is true for the gene for toll-likereceptor 7, researchers reported in Science Immunology in 2018. That canlead to more of the protein being made, giving females more guards looking outfor intruders.

Having more toll-likereceptor 7 can help jump start and enhance the next steps of the innate immune system.You want fast recognition, you want fast responses, Klein says. This is howyou start to activate the army of immune responses that are going to be neededto clear an infection. One of those steps is the release of interferons,proteins that direct major factions of the bodys immune response. In studiesthat measure levels of interferons in blood or in cells grown in a dish, researchersoverall see greater production of these interferons in females as comparedwith males, says Klein.

As the adaptive immunesystem gears up, women can get a boost over men again. The amount of antibodyproduced, as well as the quality of those antibodies, or the strength withwhich they bind to the virus, tends to be greater in females compared withmales, Klein says. Female mice produced more neutralizing antibodies the type which stop an infection by preventing thevirus from entering cells and more total antibodies against influenza A virus after infection comparedwith males, Klein and colleagues reported in Vaccine in 2011.

The female hormone estrogenalso influences the innate and adaptive immune systems. The hormone can regulatea variety of different genes for immune system proteins. For example, estrogen canstimulate the production of interferons, says Klein. And some of the genes thatare associated with directing the response of B cells, which make antibodies,are regulated by estrogen.

All of these findings comefrom research with other viruses, and havent yet been studied in the contextof COVID-19, Klein says, but they provide us with some clues. At this point,some of the best clues as to why there are discrepancies in how men and womenfare with COVID-19 may come from a study of the disease SARS in mice. The virus that causes SARS shares similarities with the culprit behind COVID-19,SARS-CoV-2 (SN: 2/3/20). And there isevidence that during the SARS epidemic of 2002-2003, which had close to 800deaths, men had a higher case fatality rate than women.

Its helpful to study sexdifferences in mice because it takes behavioral influences out of the equation,says Stanley Perlman, a virologist at the University of Iowa in Iowa City. Forexample, as reports from China indicated that more men than women were havingsevere cases of COVID-19, some also noted this could be due to the fact thatmore Chinese men than women smoke. China was also among the five countries thatSARS cases were concentrated in.

Perlmans team compared how male and female mice did when infected with a mouse-adapted version of SARS-CoV,the virus that causes SARS, and reported the results in the Journal of Immunology in 2017. Among middle-agedmice, those 8 to 9 months old, all of the males died within eight days of beinginfected, but only 10 percent of the females did by day 12. Males had higheramounts of the virus in their lungs than females did, suggesting the maleswerent clearing the virus effectively. The males also had a prolonged,unhelpful inflammatory response.

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When the research teamremoved the ovaries from 12 female mice to prevent estrogen from being made, about85 percent of the mice died after infection, compared with close to 20 percentof 12 females with their ovaries. Without estrogen, the female mice were nowas sensitive to the infection as male mice, Perlman says. While I wouldntclaim its the whole story, estrogen is a big part of the story.

Klein and Perlman both haveplans to study differences in the male and female response to COVID-19. In caseswhen the bodys own immune response contributes to a viral disease, it might beexpected women would fare worse, Klein says, because a strong immune responsecan lead to too much damaging inflammation. And with COVID-19, theres a lot ofconcern about the detrimental effect of increased inflammation in the lungs.

But what happens during COVID-19might be different. This aberrant inflammation might be higher in males thanfemales, Klein says.

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COVID-19 kills more men than women. The immune system may be why - Science News

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