Androgen exposure potentiates formation of intratubular communities and renal abscesses by Escherichia coli

Abstract

Females across their lifespan and certain male populations are susceptible to urinary tract infections (UTI). The influence of female vs. male sex on UTI is incompletely understood, in part because preclinical modeling has been performed almost exclusively in female mice. Here, we employed established and new mouse models of UTI with uropathogenic Escherichia coli (UPEC) to investigate androgen influence on UTI pathogenesis. Susceptibility to UPEC UTI in both male and female hosts was potentiated with 5α-dihydrotestosterone, while males with androgen receptor deficiency and androgenized females treated with the androgen receptor antagonist enzalutamide were protected from severe pyelonephritis. In androgenized females and in males, UPEC formed dense intratubular, biofilm-like communities, some of which were sheltered from infiltrating leukocytes by the tubular epithelium and by peritubular fibrosis. Abscesses were nucleated by small intratubular collections of UPEC first visualized at five days postinfection and briskly expanded over the subsequent 24 hours. Male mice deficient in Toll-like receptor 4, which fail to contain UPEC within abscesses, were susceptible to lethal dissemination. Thus, androgen receptor activation imparts susceptibility to severe upper-tract UTI in both female and male murine hosts. Visualization of intratubular UPEC communities illuminates early renal abscess pathogenesis and the role of abscess formation in preventing dissemination of infection. Additionally, our study suggests that androgen modulation may represent a novel therapeutic route to combat recalcitrant or recurrent UTI in a range of patient populations.

TGFβ1 orchestrates renal fibrosis following Escherichia coli pyelonephritis

“…In the present work, we utilized non-refluxing C57BL/6 mice, which develop pyelonephritis of more modest severity after UPEC inoculation of the bladder. As we reported in the C3H background (Olson et al, 2016(Olson et al, , 2018, androgen exposure was here found also to increase the rate of high-titer pyelonephritis in C57BL/6 mice. Compared with the extensive scars formed in UPEC-infected C3H mice (Olson et al, 2017), the BL/6 background enabled us to model of more limited renal scar formation, without overwhelming inflammation, and offers many more readily available genetic tools to enable future investigation.…”

“…Tgfb1 transcription was increased in TC‐treated mice early in infection, with elevated TGFβ1 production observed in TC‐treated mice was most evident in epithelial cells, predominantly in the distal nephron, earlier in infection (up to 7 dpi) and then in non‐epithelial (CD45−, E‐cadherin−) cell types later in infection (7–28 dpi). This sequence is logical, as renal epithelial surfaces are likely contacted earliest by UPEC during ascending infection (Li et al, 2017; Olson et al, 2018). Thus, epithelial TGFβ1 signaling is likely the initiator of the fibrotic response to infection; in other models, TGFβ1 signaling from epithelial cells alone is sufficient to drive a fibrotic response to injury (Gentle et al, 2013; Olson et al, 2018).…”

“…This sequence is logical, as renal epithelial surfaces are likely contacted earliest by UPEC during ascending infection (Li et al, 2017; Olson et al, 2018). Thus, epithelial TGFβ1 signaling is likely the initiator of the fibrotic response to infection; in other models, TGFβ1 signaling from epithelial cells alone is sufficient to drive a fibrotic response to injury (Gentle et al, 2013; Olson et al, 2018).…”

“…Although phosphorylation of Smad2 and Smad3 is required for these transcription factors to translocate to the nucleus and promote transcription of ECM components (Meng et al, 2016), we were unable to successfully quantify phospho-Smad2/3 in the whole kidney despite several approaches. In contrast to other experimental renal injuries that are global (e.g., UUO), experimental pyelonephritis is a localized process, affecting only a limited portion of the kidney (Olson et al, 2016(Olson et al, , 2017(Olson et al, , 2018; as outlined above, this is particularly true in the BL/6 host and thereby limits our ability to discern changes in such analytes through analysis of whole-kidney homogenates. Further work will need to be done to demonstrate phospho-Smad2/3 F I G U R E 7 Activated myofibroblasts are localized to regions of scarring in TC-treated mice.…”

“…Testosterone signaling through the androgen receptor increases susceptibility to, and severity of, experimental UPEC pyelonephritis in both male and female mice (Olson, Hruska, & Hunstad, 2016), while anti-androgen therapy is protective against severe UTI in mice (Olson et al, 2017) and in women with polycystic ovary syndrome (Gamal, Elkholi, & Nagy, 2016;Wang, Su, Liu, Chang, & Chen, 2005), a common hyperandrogenic condition. As observed in children, mice with severe pyelonephritis develop renal fibrosis and scarring (Olson et al, 2018). In non-infectious models of renal injury, fibrosis is caused by excess extracellular matrix (ECM) deposition by α-smooth muscle actin (αSMA)-positive activated myofibroblasts.…”