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 2

Females exhibit a more robust cytokine response to E.

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Females exhibit a more robust cytokine response to E. colithan males. (...
colithan males. (A–C) Female and male mice were instilled with PBS or infected with 1 × 107 CFU of UPEC strain UTI89-RFP-kanR or UTI89-GFP-ampR and sacrificed 24 or 48 hours PI. Thirty-two cytokines were measured in homogenized bladders by Luminex assay. (A) The heatmap shows unsupervised hierarchical clustering of the 21 significantly different analytes determined by ANOVA (FDR-adjusted P value to correct for multiple testing; q < 0.05, P and q values for each cytokine are shown in Table 1) among PBS-treated and UPEC-infected female and male mice. (B and C) Spider plots show absolute cytokine expression levels (pg/mL) on a log scale at (B) 24 hours PI in PBS-treated (dotted lines) and UPEC-infected female (solid red lines) and male (solid blue lines) mice and (C) 48 hours PI in both sexes (solid red or blue lines) or in naive, untreated female and male animals (dotted red or blue lines). Data are pooled from 4 experiments, n = 5–7 mice per experiment. (D and E) Analysis was performed on a publically available data set of the transcriptional response in whole blood after stimulation with heat-killed E. coli from 300 female and 300 male healthy donors, 20–49 years old. (D) The PCA plot represents the variance among 275 genes that are significantly differentially expressed between women (red dots, each dot is a donor) and men (blue dots, each dot is a donor) as determined by ANOVA, q < 0.01. (E) The mRNA expression level in each donor for CXCL2, IL-8, IL-1α, and LIF was overlaid on the PCA plot shown in D as a heatmap, in which red represents higher gene expression and green represents lower gene expression.