Abstract
The structural and functional destruction of the blood-testis barrier (BTB) following uropathogenic E. coli (UPEC) infection may be a critical component of the pathologic progress of orchitis. Recent findings indicate that the mammalian target of the rapamycin (mTOR)-signaling pathway is implicated in the regulation of BTB assembly and restructuring. To explore the mechanisms underlying BTB damage induced by UPEC infection, we analyzed BTB integrity and the involvement of the mTOR-signaling pathway using in vivo and in vitro UPEC-infection models. We initially confirmed that soluble virulent factors secreted from UPEC trigger a stress response in Sertoli cells and disturb adjacent cell junctions via down-regulation of junctional proteins, including occludin, zonula occludens-1 (ZO-1), F-actin, connexin-43 (CX-43), β-catenin, and N-cadherin. The BTB was ultimately disrupted in UPEC-infected rat testes, and blood samples from UPEC-induced orchitis in these animals were positive for anti-sperm antibodies. Furthermore, we herein also demonstrated that mTOR complex 1 (mTORC1) over-activation and mTORC2 suppression contributed to the disturbance in the balance between BTB “opening” and “closing.” More importantly, rapamycin (a specific mTORC1 inhibitor) significantly restored the expression of cell-junction proteins and exerted a protective effect on the BTB during UPEC infection. We further confirmed that short-term treatment with rapamycin did not aggravate spermatogenic degeneration in infected rats. Collectively, this study showed an association between abnormal activation of the mTOR-signaling pathway and BTB impairment during UPEC-induced orchitis, which may provide new insights into a potential treatment strategy for testicular infection.
Highlights
6% to 15% of male infertility is attributed to infections or inflammation of the urogenital tract [1]
Considering the role of mammalian target of the rapamycin (mTOR) signaling on blood-testis barrier (BTB) regulation, we evaluated the possibility of restoring the mTORC1mTORC2 balance and the expression of junctional proteins in Sertoli cells using the mTOR complex 1 (mTORC1)-specific inhibitor rapamycin (Figure 5)
We previously demonstrated that the BTB appeared to remain functionally intact at one single time-point in the early stage of uropathogenic E. coli (UPEC) infection [21]
Summary
6% to 15% of male infertility is attributed to infections or inflammation of the urogenital tract [1]. Uropathogenic Escherichia coli (UPEC) is one of the major pathogens involved in ascending, nonsexually transmitted epididymo-orchitis [2,3,4]. The elimination of invading pathogens by antibiotic administration is currently the major standardized therapy prescribed in acute bacterial epididymo-orchitis [4,5,6]. In most cases antibiotic treatment alone cannot guarantee the full restoration of fertility due to permanent tissue damage or immunologic impairment within these organs [2, 6, 7]. A better understanding of the mechanisms by which uropathogen-related orchitis disturbs testes functions may assist clinicians in developing better treatment strategies for fertility protection
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