您现在的位置:首页> 外文学位 >文献详情

【6h】The Characterization of Novel Transgenic Murine Models of Neisseria gonorrhoeae Infection and Development of a Natural Outer Membrane Vesicle Anti-Gonococcal Vaccine Candidate

机译淋病奈瑟氏球菌感染的新型转基因小鼠模型的表征和天然外膜囊泡抗淋球菌疫苗候选物的开发

【摘要】Untreatable gonorrhea, caused by fully antimicrobial resistant Neisseria gonorrhoeae (GC), is a major global health threat. While a vaccine would greatly help address this crisis, development of a GC vaccine is complicated by the lack of lab models of symptomatic gonorrhea. We hypothesized that overt disease in animal models of gonorrhea is limited by the human-restriction of gonococcal virulence factors, and the impact of the reproductive hormone cycle (estrus and diestrus phases). We tested these hypotheses by examining the host response to infection in transgenic mice expressing targets of bacterial adhesion, human carcinoembryonic antigen-related cell adhesion molecules (hCEACAMs), in uterine versus vaginal infections, and in different phases of the reproductive cycle (estrus and diestrus phases). hCEACAM expression most impacted estrus phase infections, prolonging colonization in vaginal infection and inducing greater inflammation in uterine. Reproductive phase greatly influenced host response to uterine infection as diestrus infection was more inflammatory than estrus. Phase differences in uterine infection were driven by greater activation of a chemokine-centric common anti gonococcal response and unique induction of type 1 interferons in diestrus. These findings suggest that symptomatic uterine and vaginal GC infection can be modeled by transcervically infected wild-type diestrus mice and transgenic, vaginally-infected estrus mice, respectively.;A novel approach to GC vaccine development is also needed. Mono-antigenic vaccines have failed to produce immunity suggesting a poly-antigenic antigen, like natural outer membrane vesicles (nOMVs) may be necessary. It has been shown that any GC vaccine must lack the bacterioprotective antigen, reduction modifiable protein (RMP), and no such nOMV has been previously described. Here we report successful isolation of RMP-deficient nOMVs through sequential size and weight restrictive filtration. Vesicle morphology, proteomics, and bioactivity was characterized via various methods. nOMVs were found to be consistent in size, shape and antigenic load. As antigens, nOMVs induced high serum titers and measurable vaginal levels of antigen and GC specific IgG that recognized several nOMV immunogens supporting the vaccine potential of GC nOMVs. These findings lay the groundwork for protective studies of nOMV vaccines in novel models of active gonorrhea moving the field closer to discovering the mechanism of protective anti-gonococcal immunity.

【摘要机译】完全耐药的淋病奈瑟氏球菌(GC)引起的不可治疗的淋病是全球主要的健康威胁。尽管疫苗将大大有助于解决这一危机,但由于缺乏有症状的淋病实验室模型,GC疫苗的开发变得复杂。我们假设淋病动物模型中的明显疾病受到淋球菌致病因子的人为限制以及生殖激素循环(发情期和发情期)的影响。我们通过检查宿主对表达细菌粘附,人类癌胚抗原相关细胞粘附分子(hCEACAMs),子宫和阴道感染以及生殖周期不同阶段(发情和发情期)的转基因小鼠对感染的反应来检验这些假设阶段)。 hCEACAM的表达对发情期感染的影响最大,延长了阴道感染的定植时间,并在子宫内引发了更大的炎症。生殖阶段极大地影响了宿主对子宫感染的反应,因为雌激素感染比发情更易发炎。子宫感染的相差是由趋化因子为中心的共同抗淋球菌反应的更大激活和二元组中1型干扰素的独特诱导所驱动的。这些发现表明,症状性子宫感染和阴道GC感染可以分别通过经宫颈感染的野生型雌性小鼠和转基因的,经阴道感染的发情小鼠进行建模。还需要一种新的GC疫苗开发方法。单抗原疫苗未能产生免疫力,表明可能需要像天然外膜囊泡(nOMV)这样的多抗原抗原。已经表明,任何GC疫苗都必须缺乏细菌保护性抗原,还原修饰蛋白(RMP),并且以前没有描述过这种nOMV。在这里,我们报告通过顺序大小和重量限制过滤成功分离出RMP缺陷型nOMV。通过各种方法表征囊泡的形态,蛋白质组学和生物活性。发现nOMV在大小,形状和抗原负荷方面是一致的。作为抗原,nOMV诱导了较高的血清滴度以及可测量的阴道抗原和GC特异性IgG的水平,这些抗原识别了几种支持GC nOMV疫苗潜力的nOMV免疫原。这些发现为主动淋病的新型模型中的nOMV疫苗的保护性研究奠定了基础,使该领域更加接近发现保护性抗淋球菌免疫的机制。

【作者】Francis, Ian P.;

【作者单位】Boston University.;

【年(卷),期】2020(),

【年度】2020

【页码】202 p.

【总页数】202

【正文语种】eng

【中图分类】;

【关键词】

  • 相关文献