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Sex differences in IL-17 contribute to chronicity in male versus female urinary tract infection
Anna Zychlinsky Scharff, Matthieu Rousseau, Livia Lacerda Mariano, Tracy Canton, Camila Rosat Consiglio, Matthew L. Albert, Magnus Fontes, Darragh Duffy, Molly A. Ingersoll
Anna Zychlinsky Scharff, Matthieu Rousseau, Livia Lacerda Mariano, Tracy Canton, Camila Rosat Consiglio, Matthew L. Albert, Magnus Fontes, Darragh Duffy, Molly A. Ingersoll
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Research Article Immunology Infectious disease

Sex differences in IL-17 contribute to chronicity in male versus female urinary tract infection

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Abstract

Sex-based differences influence incidence and outcome of infectious disease. Women have a significantly greater incidence of urinary tract infection (UTI) than men, yet, conversely, male UTI is more persistent, with greater associated morbidity. Mechanisms underlying these sex-based differences are unknown, in part due to a lack of experimental models. We optimized a model to transurethrally infect male mice and directly compared UTI in both sexes. Although both sexes were initially equally colonized by uropathogenic E. coli, only male and testosterone-treated female mice remained chronically infected for up to 4 weeks. Female mice had more robust innate responses, including higher IL-17 expression, and increased γδ T cells and group 3 innate lymphoid cells in the bladder following infection. Accordingly, neutralizing IL-17 abolished resolution in female mice, identifying a cytokine pathway necessary for bacterial clearance. Our findings support the concept that sex-based responses to UTI contribute to impaired innate immunity in males and provide a rationale for non–antibiotic-based immune targeting to improve the response to UTI.

Authors

Anna Zychlinsky Scharff, Matthieu Rousseau, Livia Lacerda Mariano, Tracy Canton, Camila Rosat Consiglio, Matthew L. Albert, Magnus Fontes, Darragh Duffy, Molly A. Ingersoll

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Figure 7

IL-17 is necessary for resolution of infection in female mice.

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IL-17 is necessary for resolution of infection in female mice.
(A) Femal...
(A) Female and male mice were infected with 1 × 107 CFU of UPEC strain UTI89-RFP-kanR and bladders analyzed by flow cytometry at 24 hours PI. Graphs show (A) the number of CD3+CD4+ T cells, CD3–NK1.1+ NK cells, γδ T cells, and CD4+ ILC3s (CD90+CD25+CD4+CD3–NK1.1–MHC II–CD11b–) in bladders. (B) Female mice were implanted with empty tubing (Mock) or slow-release tubing containing testosterone (T tube) and allowed to recover 1 week before infection with 1 × 107 CFU UPEC strain UTI89-RFP-kanR. Graphs show the number of CD3+CD4+ T cells, CD3–NK1.1+ NK cells, γδ T cells, and CD4+ ILC3s (CD90+CD25+CD4+CD3–NK1.1–MHC II–CD11b–) in bladders. (C–E) Graphs show the number of infected female mice, determined by urine sampling, over time in (C) wild-type or RAG2–/–γc mice, (D) mice treated with isotype or NK1.1-depleting antibody, (E) mice treated with IL-17–neutralizing antibody. (A and B) Data are pooled from 2–3 experiments, n = 4–5/group in each experiment. Each dot is 1 mouse, red dots depict female mice and blue dots are male mice, and lines are medians. In C–E, graphs are representative experiments, n = 6–12 mice per experiment, 2–3 experiments each. In A, *P < 0.05, **P < 0.01 by Kruskal-Wallis test comparing female naive with male naive, female naive with female infected, male naive with male infected, and female infected with male infected, with Dunn’s post hoc test to correct for multiple comparisons. In B, Mann-Whitney test was used with correction for multiple testing by the Holm–Bonferroni method; all P < 0.05 had q < 0.05.

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