ME/CFS Science Blog
Senior Member (Voting Rights)
Have little to add except that it looks really interesting. Made this summary of the results in case it is helpful to anyone.
1) Impressive study from Johns Hopkins researchers. They infected mice with SARS-CoV-2, found that female mice had a stronger immune response and more cognitive problems after 84 days than males, and that this was due to overexpression of genes such as Tlr7 on the X chromosome.
2) The study tries to answer the paradox of why males are more likely to be severely ill during infection, while females are more likely to develop Long Covid. They confirmed this pattern in mice: males had more severe acute illness while females had more lingering cognitive problems.
3) The working memory of the mice was tested through various behavioural tests. There was also a control group of females without infection. Yet only the infected females did worse on maze, marble burying, and novel object recognition tests.
4) The researchers could demonstrate that this sex difference was unlikely to be due to the amount of virus in the body. Males and females did not differ in their ability to control viral replication or clear the SARS-CoV-2 virus.
5) There was, however, a difference in inflammatory immune response as measured in the lungs and spleen during and after infection. Females had more cytokines, such as TNF-α, IL-6, IL-1β, CCL2, CCL3, and CCL4, which are involved in the activation and recruitment of myeloid cells.
6) Females also had signs of T cell dysregulation after recovery from acute SARS-CoV-2 infection. For example, they had greater frequencies of Tregs and lower CD4+ helper T cell frequencies compared to infected males.
7) Next, the researchers checked for neuroinflammation. Across the entire brain, there were no significant differences in cytokine and chemokine concentrations. But in the hippocampus, there were more activated microglia in infected females than in males.
8) There were no sex differences in the percentage of mature neurons or the number of immature neurons. So, the cognitive issues in female mice were likely not caused by damage or impaired neurogenesis in the hippocampus.
9) Now it becomes interesting. While males have an X and a Y chromosome, females have two Xs. The authors wanted to know what’s causing the sex difference in the response to SARS-CoV-2.
10) So they created genetically altered mice with different combinations of sex chromosomes:
XX (normal female: XX chromosomes + ovaries)
X0 (one X chromosome + ovaries)
XY (normal male: XY chromosomes + testicles)
XXY (XXY chromosomes + testicles).
11) They redid the experiments with these new genetically altered mice. This allowed the researchers to separate the effects of the number of X chromosomes from the presence or absence of the Y chromosome.
Turns out it's the number of X chromosomes that matters.
12) The authors found that the prolonged activation of myeloid cells is mediated by the number of X chromosomes. They then looked at genes on the X chromosome that might explain this.
13) They found that expression of Xist was increased in immune cells from infected compared to mock-infected females, while it was not expressed in males. Normally, one of the two X chromosomes in females is silenced, and Xist regulates this process.
14) So one idea is that this silencing of one of the X chromosomes is disrupted after infection, so that some X genes are over-expressed, causing a stronger immune response in females.
15) The authors found immune-related genes on the X chromosome, such as Tlr7, to have increased expression in infected female mice. So it could be that these explain the stronger immune response and increased susceptibility to Long Covid in females.
16) A fascinating study, but there are some important caveats. The sample size, the number of mice per group, was quite low (around 10), and the statistical analysis did not correct for the number of comparisons they made across all their experiments.
17) There were also behavioral and cognitive tests that did not show a significant difference between infected males and females. An example is the tail-suspension test, where the time mice spent immobile was the same for both sexes.
18) Lastly, humans are not mice, so the experiments and findings may not apply to us. The maze and object recognition test may be poor proxies for cognitive problems in Long Covid. Even so, the sex difference in the immune response to SARS-CoV-2 may be helpful in understanding PAIS.
1) Impressive study from Johns Hopkins researchers. They infected mice with SARS-CoV-2, found that female mice had a stronger immune response and more cognitive problems after 84 days than males, and that this was due to overexpression of genes such as Tlr7 on the X chromosome.
2) The study tries to answer the paradox of why males are more likely to be severely ill during infection, while females are more likely to develop Long Covid. They confirmed this pattern in mice: males had more severe acute illness while females had more lingering cognitive problems.
3) The working memory of the mice was tested through various behavioural tests. There was also a control group of females without infection. Yet only the infected females did worse on maze, marble burying, and novel object recognition tests.
4) The researchers could demonstrate that this sex difference was unlikely to be due to the amount of virus in the body. Males and females did not differ in their ability to control viral replication or clear the SARS-CoV-2 virus.
5) There was, however, a difference in inflammatory immune response as measured in the lungs and spleen during and after infection. Females had more cytokines, such as TNF-α, IL-6, IL-1β, CCL2, CCL3, and CCL4, which are involved in the activation and recruitment of myeloid cells.
6) Females also had signs of T cell dysregulation after recovery from acute SARS-CoV-2 infection. For example, they had greater frequencies of Tregs and lower CD4+ helper T cell frequencies compared to infected males.
7) Next, the researchers checked for neuroinflammation. Across the entire brain, there were no significant differences in cytokine and chemokine concentrations. But in the hippocampus, there were more activated microglia in infected females than in males.
8) There were no sex differences in the percentage of mature neurons or the number of immature neurons. So, the cognitive issues in female mice were likely not caused by damage or impaired neurogenesis in the hippocampus.
9) Now it becomes interesting. While males have an X and a Y chromosome, females have two Xs. The authors wanted to know what’s causing the sex difference in the response to SARS-CoV-2.
10) So they created genetically altered mice with different combinations of sex chromosomes:
XX (normal female: XX chromosomes + ovaries)
X0 (one X chromosome + ovaries)
XY (normal male: XY chromosomes + testicles)
XXY (XXY chromosomes + testicles).
11) They redid the experiments with these new genetically altered mice. This allowed the researchers to separate the effects of the number of X chromosomes from the presence or absence of the Y chromosome.
Turns out it's the number of X chromosomes that matters.
12) The authors found that the prolonged activation of myeloid cells is mediated by the number of X chromosomes. They then looked at genes on the X chromosome that might explain this.
13) They found that expression of Xist was increased in immune cells from infected compared to mock-infected females, while it was not expressed in males. Normally, one of the two X chromosomes in females is silenced, and Xist regulates this process.
14) So one idea is that this silencing of one of the X chromosomes is disrupted after infection, so that some X genes are over-expressed, causing a stronger immune response in females.
15) The authors found immune-related genes on the X chromosome, such as Tlr7, to have increased expression in infected female mice. So it could be that these explain the stronger immune response and increased susceptibility to Long Covid in females.
16) A fascinating study, but there are some important caveats. The sample size, the number of mice per group, was quite low (around 10), and the statistical analysis did not correct for the number of comparisons they made across all their experiments.
17) There were also behavioral and cognitive tests that did not show a significant difference between infected males and females. An example is the tail-suspension test, where the time mice spent immobile was the same for both sexes.
18) Lastly, humans are not mice, so the experiments and findings may not apply to us. The maze and object recognition test may be poor proxies for cognitive problems in Long Covid. Even so, the sex difference in the immune response to SARS-CoV-2 may be helpful in understanding PAIS.