Development of a model of Gonococcal conjunctivitis for vaccine evaluations

摘要 卫生保健界对目前世界范围内N。淋病感染 在传染病、微生物学和免疫学领域， 和文学。世界范围内淋球菌感染的主要表现是生殖道感染， 结膜炎，后者是低收入和中等收入国家出生的婴儿的主要问题，被诊断为OPH， 尿道炎由于抗微生物剂耐药性， 泛耐药、不可治疗的GC感染的威胁很高。因此，新的办法、战略和工具正在 需要解决这个极其成功的人类病原体的后果。在这个列表的顶部 是控制GC感染和传播的疫苗和免疫治疗剂。然而，与它的表亲N.男人- 疫苗可预防的疾病已经通过靶向免疫原性、血清学 可变的荚膜多糖或最近的血清群B的表面蛋白，这样的疫苗靶标具有 在N上未被识别。淋病细胞事实上，没有已知的人类免疫介导的相关性， 抗GC感染。此外，再感染N.淋病似乎经常发生， 表明疫苗抗原在血清学上是可变的，并且在菌株之间或感染之间存在显著差异， GC不能产生足够的保护性免疫反应。 本研究的目的是建立和验证一种小鼠N.淋病性结膜炎 成年小鼠和新生小鼠，以在方便的实验室中研究对该病原体的毒力和免疫力 动物模型第二个目标是评估抗体疗法的预防和治疗潜力。 Tips to N.淋病，以证实结膜感染模型对此类研究的实用性。这些目标 包括我们已经展示的保守的细菌表面多糖聚-N-乙酰葡糖胺（PNAG 围绕N的外表面。淋病，并作为杀菌抗体的目标，表面 单克隆抗体（MAb）2C 7识别的脂寡糖（LOS）。 我们建议利用我们丰富的经验，与小鼠模型的眼部感染，研究N。 淋病性结膜炎在成年和新生小鼠。我们将确定生长和剂量参数 需要在这两种小鼠环境中建立感染，后者作为结膜炎的模型。 我们将评估多发性N。淋病菌株，测试主动和被动免疫疗法， 影响细菌负荷和结膜病理，并确定一些体外和体内免疫 影响这些感染和疾病指标的效应物。如果成功， 容易研究其他疫苗和疗法，以及毒力因子和宿主先天性和获得性免疫， 社区N。淋病在临床相关的设置。因此，GC结膜炎的体内鼠模型 感染将填补目前限制对N.淋病感染

Abstract The serious concerns of the health-care community around the current state of worldwide N. gonorrhoeae infec- tions are well known and documented in the infectious diseases, microbiology and immunology communities and literature. The major manifestations of gonococcal (GC) infection worldwide are genital tract infections and conjunctivitis, the latter a major problem in infants born in low and middle income countries, diagnosed as oph- thalmia neonatorum. There is a global concern about effective treatments due to antimicrobial resistance and the threat of pan-resistant, untreatable GC infections is high. Thus, new approaches, strategies and tools are needed to address the consequences from this exceedingly successful human pathogen. At the top of this list are vaccines and immunotherapeutics to control GC infection and transmission. Yet, unlike its cousin, N. men- ingitides, where vaccine-preventable disease has been obtained by targeting the immunogenic, serologically variable capsular polysaccharides or, more recently, surface proteins for serogroup B, such vaccine targets have not been identified on N. gonorrhoeae cells. Indeed, there are no known correlates of human immunity mediating resistance to GC infection. Furthermore, reinfection with N. gonorrhoeae seems to occur sufficiently frequently to suggest that vaccine antigens are either serologically variable and differ markedly among strains, or, infection with GC simply does not engender sufficient protective immune responses. The goal of this research project is to develop and validate a murine model of N. gonorrhoeae conjunctivitis in both adult and neonatal mice to study virulence and immunity to this pathogen in a readily accessible laboratory animal model. A second goal will be to evaluate the prophylactic and therapeutic potential of antibody therapeu- tics to N. gonorrhoeae to substantiate the utility of the conjunctival infection model for such studies. These targets include the conserved bacterial surface polysaccharide poly-N-acetyl glucosamine (PNAG) that we have shown surrounds the outer surface of N. gonorrhoeae and serves as a target for bactericidal antibody, and the surface lipooligosaccharide (LOS) recognized by monoclonal antibody (MAb) 2C7. We propose to take advantage of our extensive experience with murine models of ocular infections to study N. gonorrhoeae conjunctivitis in adult and neonatal mice. We will determine the growth and dose parameters needed to establish infection in both of these murine settings, the latter as a model for ophthalmia neonatorum. We will evaluate pathogenesis of multiple N. gonorrhoeae strains, test active and passive immunotherapies for impacting bacterial burdens and conjunctival pathology, and determine some of the in vitro and in vivo immune effectors needed to impact these measures of infection and disease. Success would open up the potential to readily study additional vaccines and therapies, as well as virulence factors and host innate and acquired im- munity to N. gonorrhoeae in a clinically-relevant setting. Thus, an in vivo murine model for GC conjunctival infection would fill in the gaps currently limiting the study of virulence and immunity to N. gonorrhoeae infections.