Department of Microbiology, Virginia Commonwealth University Medical Center, Richmond, Virginia 232981, USA.
Infect Immun. 2011 Dec;79(12):4764-76. doi: 10.1128/IAI.05806-11. Epub 2011 Sep 26.
Neisseria gonorrhoeae is an obligate human pathogen that causes the common sexually transmitted infection gonorrhea. Gonococcal infections cause significant morbidity, particularly among women, as the organism ascends to the upper reproductive tract, resulting in pelvic inflammatory disease, ectopic pregnancy, and infertility. In the last few years, antibiotic resistance rates have risen dramatically, leading to severe restriction of treatment options for gonococcal disease. Gonococcal infections do not elicit protective immunity, nor is there an effective vaccine to prevent the disease. Thus, further understanding of the expression, function, and regulation of surface antigens could lead to better treatment and prevention modalities in the future. In the current study, we determined that an iron-repressed regulator, MpeR, interacted specifically with the DNA sequence upstream of fetA and activated FetA expression. Interestingly, MpeR was previously shown to regulate the expression of gonococcal antimicrobial efflux systems. We confirmed that the outer membrane transporter FetA allows gonococcal strain FA1090 to utilize the xenosiderophore ferric enterobactin as an iron source. However, we further demonstrated that FetA has an extended range of substrates that encompasses other catecholate xenosiderophores, including ferric salmochelin and the dimers and trimers of dihydroxybenzoylserine. We demonstrated that fetA is part of an iron-repressed, MpeR-activated operon which putatively encodes other iron transport proteins. This is the first study to describe a regulatory linkage between antimicrobial efflux and iron transport in N. gonorrhoeae. The regulatory nidus that links these systems, MpeR, is expressed exclusively by pathogenic neisseriae and is therefore expected to be an important virulence factor.
淋病奈瑟菌是一种专性人类病原体，可引起常见的性传播感染淋病。淋球菌感染会导致严重的发病率，尤其是在女性中，因为该病原体向上生殖道上升，导致盆腔炎、宫外孕和不孕。在过去的几年中，抗生素耐药率急剧上升，导致淋病治疗选择严重受限。淋球菌感染不会引起保护性免疫，也没有有效的疫苗来预防这种疾病。因此，进一步了解表面抗原的表达、功能和调节可能会导致未来更好的治疗和预防方法。在当前的研究中，我们确定了一种铁抑制调节因子 MpeR，它与 fetA 上游的 DNA 序列特异性相互作用并激活 FetA 的表达。有趣的是，MpeR 先前被证明调节淋病球菌抗菌外排系统的表达。我们证实，外膜转运蛋白 FetA 允许淋病球菌菌株 FA1090 利用外源性铁载体三价铁 enterobactin 作为铁源。然而，我们进一步证明 FetA 具有更广泛的底物范围，包括其他儿茶酚外源性铁载体，如三价铁 salmochelin 和二羟基苯丙氨酸的二聚体和三聚体。我们证明 fetA 是一个铁抑制、MpeR 激活操纵子的一部分，该操纵子可能编码其他铁转运蛋白。这是首次描述淋病奈瑟菌中抗菌外排和铁转运之间的调节联系。将这些系统联系起来的调节中心 MpeR 仅由致病性奈瑟菌表达，因此预计是一个重要的毒力因子。
