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

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 1

Male mice do not resolve UTI following intravesical instillation.

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Male mice do not resolve UTI following intravesical instillation. (A and...
(A and B) Seven-week-old female and male C57BL/6J mice were infected with 1 × 107 CFU of UPEC strain UTI89-RFP-kanR or UTI89-GFP-ampR. Graphs depict (A) the number of infected mice, determined by urine sampling, and (B) CFU/bladder. (C) Schematic of the experiment depicted in D: female and male C57BL/6J mice were infected with 1 × 107 CFU of UPEC strain UTI89-GFP-ampR and bladder bacterial burden was determined 24 hours after primary (1°) infection. At 29 days postinfection (PI), all animals were treated with antibiotics (abx) for 5 days, followed by a 7-day wash-out period. After determination that all mice had sterile urine, mice were challenged with 1 × 107 CFU UPEC strain UTI89-RFP-kanR and CFU in bladders determined at 24 hours after challenge (2°) infection. (D) The graph shows bacterial CFU at 24 hours after primary or challenge infection in the bladder. A depicts representative data (n = 10 female, n = 9 male) from 1 of more than 5 experiments; red is female, blue is male. Data in B and D are pooled from 2–4 experiments, n = 6–10 mice/group in each experiment. Each dot represents 1 mouse, red denotes female mice and blue indicates male mice, and lines are medians. Dotted lines depict the limit of detection of the assay, 20 CFU/bladder. In B, ****P < 0.0001, Kruskal-Wallis test comparing female to male at each time point, with Dunn’s post hoc test to correct for multiple comparisons. In D, **P < 0.01, ns = not significant, Kruskal-Wallis test comparing 1° with 2° infection within a single sex and comparing 1° or 2° CFU between sexes, with Dunn’s post hoc test to correct for multiple comparisons.