Ontogeny Of Oral Epithelial Antimicrobial Peptides

描述（由申请人提供）：先天免疫系统是一种进化上古老的反应，被认为在出生时或在生命的最初几天内就存在并发挥作用。然而，肠道细菌在“开启”先天免疫中发挥的作用;即，调节它的反应，以及在生命中的什么个体发育点开始发生这种情况尚不清楚。我们实验室最近的发现使我们推测，口腔先天免疫反应的个体发生可能与口腔中的定植生物有关。我们最近发现具核梭杆菌（Fusobacterium nucleatum），一种在人类口腔中普遍存在的革兰氏阴性细菌，诱导上皮细胞衍生的人β防御素-2（hBD-2）和hBD-3在正常口腔上皮细胞（NHOECs）中的表达，导致对牙龈卟啉单胞菌（Porphyromonas gingivalis）（牙周破坏的主要病原体）的侵袭的保护。广泛的生物化学和分子生物学工作已经确定了一个F。诱导这些抗菌和免疫调节肽的核外膜蛋白。我们将这种蛋白质称为FAD-1，用于梭菌相关防御素诱导剂。此外，初步的横断面数据表明，唾液hBD水平显着低于婴儿期比老年组。我们怀疑与hBD诱导和可能的其它上皮细胞衍生的抗菌肽（AMP）的年龄相关的关联与表达FAD-1的F.具核菌株显然，我们需要通过（1）进行流行病学研究，调查各年龄段的AMP水平，以建立总体、年龄分层和FAD-I相关的分布;（2）确定FAD-1对AMP的诱导性质及其随后对NHOEC保护的贡献，以及（3）进一步表征FAD-1的功能性。通过分子和生物化学方法初步确定hBD诱导的结构-功能关系。通过更好地了解个体先天免疫AMP谱的个体发生谱，我们可能能够识别易患粘膜感染的个体。通过发现潜在的有益的免疫策略，如FAD-I似乎是，我们可能有一天能够利用这些策略来保护敏感的粘膜部位。FAD-I是一项新发现，值得调查它或其衍生物可能为药物设计提供新方向的可能性，这些药物设计可以在当地利用，以加强大自然母亲自身的防御。

DESCRIPTION (provided by applicant): The innate immune system, an evolutionarily ancient response, is believed to be present and functional at birth or within the first few days of life. However, the role commensal bacteria play in "turning on" innate immunity; i.e., regulating it's response, and at what ontogenic point in life this begins to occur is not known. Recent findings in our laboratory are leading us to conjecture that ontogeny of the oral innate immune response may be linked to colonizing organisms in the oral cavity. We recently discovered that Fusobacterium nucleatum, a ubiquitous Gram-negative bacterium of the human oral cavity, induces expression of epithelial cell derived human beta defensin -2 (hBD-2) and hBD-3 in normal oral epithelial cells (NHOECs), resulting in protection against invasion of Porphyromonas gingivalis, a major etiologic agent in periodontal destruction. Extensive biochemical and molecular biological work has identified an F. nucleatum outer membrane protein that induces these antimicrobial and immunoregulatory peptides. We refer to this protein as FAD-I for Fusobacterial associated defensin inducer. Additionally, preliminary cross-sectional data indicates that salivary hBD levels are significantly lower in infancy than in older age groups. We suspect that an age-related association with hBD induction, and possibly other epithelial cell derived antimicrobial peptides (AMPs), is correlated with colonization and persistence of FAD-I expressing F. nucleatum strains. Clearly we need to know more about this dynamic by (1) conducting epidemiologic studies to investigate AMP levels across the age spectrum to establish overall, age stratified and FAD-I associated distributions; (2) determining the inductive properties of FAD-I on AMPs and their subsequent contribution to NHOEC protection and (3) further characterizing the functionality of FAD-I by taking molecular and biochemical approaches to ascertain preliminary structure-function relationships in hBD induction. By better understanding the ontogenic spectrum of an individual's innate immune AMP profile, we may be able to identify individuals who are predisposed to mucosal infections. By uncovering potential beneficial commensal strategies with the host, as FAD-I appears to be, we may one day be able to exploit these strategies in protecting susceptible mucosal sites. FAD-I is a new discovery that warrants investigation into the possibility that it or its derivatives may provide a new direction into drug design that could be exploited locally to bolster Mother Nature's own defenses.