The Gonococcal Fur Regulon Link to Pathogenesis

总结 淋病奈瑟菌是性传播感染（STI）淋病的病原体， 世界范围内发病率较高的疾病，每年约有1.06亿例。像许多人类病原体一样， 生物体必须适应感染期间遇到的环境，包括低pH值和变化的氧气 铁的水平。淋球菌中基因表达的严格控制部分由Fur蛋白介导， 其与特定的DNA序列结合，导致基因库的激活或抑制。 我们最近报道，淋球菌Fur调节子延伸到另外的调节蛋白， 共同促成淋球菌的发病机制。我们还确定了Fur的子集 受调节的基因在女性自然淋球菌感染期间表达， 体外 基于我们的研究结果，我们假设淋球菌Fur调节子延伸到额外的 在女性生殖道中表达和调节的调节网络。建议的研究 本申请将定义毛皮介导的调节是如何通过控制额外的 对自然感染至关重要的调节因子。我们的分析将集中在调节蛋白和sRNAs 1）通过毛皮（直接或间接）控制，2）在人类自然感染期间调节。 我们将这些称为“体内表达的淋球菌调节因子”（GREIV）。建议的目标如下： 目标1.确定毛皮控制的淋球菌调节蛋白和sRNA表达的库 在女性生殖道自然感染期间。目标2.描述新确定的 毛控型GREIV在N.淋病与上皮细胞和先天免疫细胞的相互作用。目标3： 完全确定淋球菌在女性自然感染过程中表达的全球调节网络 生殖器

Summary Neisseria gonorrhoeae is the etiological agent of the sexually transmitted infection (STI) gonorrhea, a high morbidity disease worldwide with ~ 106 million cases annually. Like many human pathogens this organism must adapt to environments encountered during infection, including low pH and varying oxygen and iron levels. Tight control of gene expression in the gonococcus is mediated in part by the Fur protein, which binds to specific DNA sequences leading to either activation or repression of a repertoire of genes. We recently reported that the gonococcal Fur regulon extends to additional regulatory proteins, which together contribute to gonococcal mechanisms of pathogenesis. We also established that subsets of Fur regulated genes are expressed during natural gonococcal infection in women relative to during growth in vitro. Based collectively on our results we hypothesize that the gonococcal Fur regulon extends to additional regulatory networks that are expressed and regulated in the female genital tract. The studies proposed in this application will define how Fur-mediated regulation is extended through control of additional regulators that are crucial to natural infection. Our analysis will focus on regulatory proteins and sRNAs that are 1) Controlled via Fur (directly or indirectly) and 2) Regulated during natural infection in humans. We term these “gonococcal regulators expressed in vivo” (GREIV). The following Aims are proposed: Aim 1. To define the repertoire of Fur-controlled gonococcal regulatory proteins and sRNAs expressed during natural infection of the female genital tract. Aim 2. To characterize the role of newly identified Fur-controlled GREIV in N. gonorrhoeae interactions with epithelial cells and innate immune cells. Aim 3. To fully define gonococcal global regulatory networks expressed during natural infection of the female genital.