Androgens Enhance Male Urinary Tract Infection Severity in a New Model

Abstract

Urinary tract infections (UTIs) occur predominantly in females but also affect substantial male patient populations; indeed, morbidity in complicated UTI is higher in males. Because of technical obstacles, preclinical modeling of UTI in male mice has been limited. We devised a minimally invasive surgical bladder inoculation technique that yields reproducible upper and lower UTI in both male and female mice, enabling studies of sex differences in these infections. Acute uropathogenic Escherichia coli (UPEC) cystitis in C57BL/6 and C3H/HeN males recapitulated the intracellular bacterial community pathway previously shown in females. However, surgically infected females of these strains exhibited more robust bladder cytokine responses and more efficient UPEC control than males. Compared with females, C3H/HeN males displayed a striking predilection for chronic cystitis, manifesting as persistent bacteriuria, high-titer bladder bacterial burdens, and chronic inflammation. Furthermore, males developed more severe pyelonephritis and 100% penetrant renal abscess (a complication that is rare in female mice). These phenotypes were sharply abrogated after castration but restored with exogenous testosterone, suggesting that male susceptibility to UTI is strongly influenced by androgen exposure. These data substantiate the long-standing presumption that anatomic differences in urogenital anatomy confer protection from UTI in males; however, as clinically observed, male sex associated with more severe UTI once these traditional anatomic barriers were bypassed. This study introduces a highly tractable preclinical model for interrogating sex differences in UTI susceptibility and pathogenesis, and illuminates an interplay between host sex and UTI that is more complex than previously appreciated.

Local Generation of Kynurenines Mediates Inhibition of Neutrophil Chemotaxis by Uropathogenic Escherichia coli

“…Specifically, TNF-␣ was shown to initiate a p38 mitogen-activated protein kinase (MAPK)-dependent "stop signal" that induces neutrophil adhesion and not polarization, resulting in diminished PMN motility toward chemoattractants (38). Existing data indicate that UPEC induces local TNF-␣ secretion during cystitis (21,50), and we show that in the bladder as a whole, TNF-␣ influences early IDO induction in response to UPEC (Fig. 5A).…”

Urinary Tract Infection: Pathogenesis and Outlook

“…Of note, instillation of uropathogens into the urethra of male mice elicits prostatic infection [111, 112]. In a recently developed, new model of UTI, a small abdominal incision is made and bacteria are inoculated via needle into the bladders of male and female mice, permitting direct sex comparisons [113]. This inoculation method recapitulates the IBC cascade of acute cystitis established in studies with catheter-infected females.…”

Uropathogens and Pyuria in Children With Neurogenic Bladders

“…There are several possible explanations for this finding. Olson et al 12 have demonstrated that male mice are more likely to develop chronic inflammation and persistent bacteriuria after UTI compared with female mice, an association that may be mediated by androgen exposure. In addition, there are several specific etiologies of neurogenic bladder that are only present in boys (eg, posterior urethral valves), or have a male predominance (eg, Eagle-Barrett syndrome).…”