Research efforts in recent years have highlighted that sex - being a woman or a man - can have a strong influence on how humans and animals respond to many types of infections. Researchers at the Institut Pasteur have identified a sex-based difference in the early immune response to infection in a model of urinary tract infection in female and male animals.
In humans, sex – being a woman or a man – influences the response to infection, and generally speaking, many types of infections are more common among men, men are more likely to become infected, and in the course of infection, men will experience more severe symptoms. There are exceptions to these generalizations, however, in which women are more susceptible to infection or experience worse symptoms over the course of a disease.
One such exception, urinary tract infection, is an exceedingly common disease thought to be largely confined to women. Reports show that adult women are 20-40 times more likely than men to have a urinary tract infection. Notably, however, this infection in a man is always classified as a complicated infection and is associated with a worse prognosis, a longer duration of treatment, and the risk of complications, such as infection of the prostate. While the reasons for the bias of this infection are not entirely clear, a new study by researchers at the Institut Pasteur has identified a sex-based difference in the early immune response to infection in a model of urinary tract infection in female and male animals.
Shedding light on the significance of sex hormones
Historically, it was proposed that differences in the prevalence of infection were due to the dissimilar anatomy of the urinary tract between women and men, such as the length of the urethra. However, this hypothesis does not take into account that young and elderly individuals of both sexes experience urinary tract infection in near equal numbers. The authors of this study postulated that sex hormones, such as testosterone, may be responsible for the differences observed in urinary tract infection between women and men. Indeed, sex hormone levels change over time, and decreases in testosterone level, for example, correlate with an increase in the prevalence of urinary tract infection in men. In addition, earlier studies have shown that sex hormones, including testosterone, estrogen, and progesterone, can impact how humans and animals respond to infection.
Testosterone’s effect on a key cytokine
In this study, led by Dr Molly Ingersoll, a researcher in the Department of Immunology at the Institut Pasteur, animals of both sexes were infected with uropathogenic E. coli, the most common cause of this bacterial infection. The immune response to infection was assessed by measuring the cells and immune mediators in infected bladders of animals of both sexes. ”We were surprised to find that while the immune response was quite strong in female mice, and these animals were able to eliminate the bacteria and resolve their infection, male mice had a much weaker immune response and developed chronic infection,” says Molly Ingersoll. Further investigation revealed that a key cytokine, which is a molecule that directs an immune response or recruits immune cells, was present in greater amounts in female mice. When the researchers inhibited this cytokine in female mice very early after infection or gave female mice testosterone, the infection become chronic. “Together, this body of work demonstrates that testosterone can dampen the immune response to urinary tract infection and may do so by specifically acting on a key molecule present early during infection” adds Molly Ingersoll. Recently awarded funding from the L’Agence nationale de la recherche (ANR), will allow Molly Ingersoll and her team the opportunity to study these pathways in greater depth.
Researchers have neglected the study of how sex influences immunity for a long time, due in part to concerns that sex hormones may influence the outcome in a study. More recent work suggests that these concerns can be mitigated or even exploited to better understand the biology of sex differences in infection and immunology. Indeed, this study highlights that including sex as a study parameter can reveal important biologic differences in early immune responses to infection between females and males, which likely go beyond the bladder. As the influence of sex on the immune response is underappreciated, studies such as this will help to expand our understanding of differences in immunity and provide a foundation for more refined therapies targeting immune-related differences between men and women.
Sex differences in IL-17 contribute to chronicity in male versus female urinary tract infection, JCI Insight, 11 juillet 2019
Anna Zychlinsky Scharff1,2, Matthieu Rousseau1,2, Livia Lacerda Mariano1,2, Tracy Canton1,2, Camila Consiglio1,2, Matthew L Albert1,2,6, Magnus Fontes3,4,5,6, Darragh Duffy1,2, Molly A Ingersoll1,2
1 Unité Immunologie des cellules dendritiques, département d’Immunologie, Institut Pasteur, 75015 Paris, France
2 INSERM U1223, 75015 Paris, France
3 International Group for Data Analysis, Institut Pasteur, 75015 Paris, France
4 The Centre for Mathematical Sciences, université de Lund, 221 00 Lund, Suède
5 The Center for Genomic Medicine, Rigshospitalet et Persimune, Copenhague, Danemark
6 Department of Cancer Immunology, Genentech Inc, South San Francisco, Californie, États-Unis