The role of iron in the course of bacterial infection of the testis

环境诱发男性不育症的一个主要原因与由淋病奈瑟菌、沙眼衣原体或尿路致病性大肠杆菌（UPEC）等细菌引起的急性感染性附睾炎有关。UPEC感染后，在感染消退后很长一段时间内也观察到附睾精子数量减少，这表明睾丸受累，生殖细胞可能受损。UPEC拥有非常广泛的铁采集系统，使其能够在极度缺铁的环境中生存。在合作准备工作中，我们已经证明铁转运蛋白在Sertoli细胞中极化，并可能参与内部铁循环，该循环为早期发育的生殖细胞提供持续的铁控制供应，以保护发育中的精子免受氧化应激和外周铁以及一般的营养波动。因此，我们假设，UPEC感染将通过UPEC引发的对宿主铁调节蛋白的操纵来扰乱睾丸铁稳态，直接影响宿主铁稳态，并且UPEC引发的睾丸铁稳态的改变有助于感染的过程和男性生育能力。为了验证这一假设，Meinhardt和Meyron-Holtz实验室，分别是男性生殖道免疫学和铁代谢方面的专家，进行了合作。我们将使用已建立的UPEC介导的附睾睾丸炎小鼠模型来测试溶血素A（溶血素A是一种对UPEC铁获取很重要的孔形成蛋白）阳性或溶血素A阴性的UPEC菌株感染如何影响这些小鼠的铁稳态、感染过程和生育参数。了解UPEC感染期间铁稳态对男性生育能力的贡献可能会导致新的治疗策略和UPEC感染后男性生育能力的改善。

A major cause for environmentally induced male infertility is related to acute infectious epididymo-orchitis elicited by bacteria such as Neisseria gonorrhoeae, Chlamydia trachomatis or the uropathogenic E. coli (UPEC). Following UPEC infection, a reduction of epididymal sperm counts was observed also long after the resolution of the infection, which suggests a testicular involvement and possible damage to germ cells. UPEC has an exceptionally large range of iron acquisition systems which enable it to survive in extremely iron poor environments. In collaborative preparatory work, we have demonstrated that iron trafficking proteins are polarized in Sertoli cells and may participate in an internal iron cycle, which provides a constant controlled supply of iron to early developing germ cells to protect the developing sperm from oxidative stress and peripheral iron as well as nutrient fluctuations in general. We thus hypothesize, that UPEC infection will perturb the testicular iron homeostasis through UPEC elicited manipulation of host-iron regulatory proteins, directly affecting the host iron homeostasis and that the UPEC-elicited shift in iron homeostasis in the testis contributes to the course of the infection and male fertility. To test this hypothesis, the Meinhardt and Meyron-Holtz labs, experts in immunology of the male reproductive tract and iron metabolism, respectively, have teamed up. We will use an established mouse-model for UPEC mediated epididymo-orchitis to test how the infection with hemolysin A (hemolysin A is a pore forming protein important for iron acquisition of UPEC) positive or hemolysin A negative UPEC-strains will affect iron homeostasis, the course of the infection and fertility parameters in these mice. Understanding the contribution of iron homeostasis to male fertility during UPEC infection may lead to novel treatment strategies and the improvement of male fertility, following UPEC infection.