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，被认为在出生或生命的最初几天就存在并起作用。然而，共生细菌在“开启”先天免疫中所起的作用；也就是说，调节它的反应，以及在生命的哪个个体发生点开始发生尚不清楚。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内的定植生物有关。我们最近发现，人类口腔中普遍存在的革兰氏阴性细菌核梭杆菌（Fusobacterium nucleatum）在正常口腔上皮细胞（NHOECs）中诱导上皮细胞源性人β防御素-2 （hBD-2）和hBD-3的表达，从而保护口腔免受牙龈卟啉单胞菌（Porphyromonas gingivalis）的侵袭，而牙龈卟啉单胞菌是牙周破坏的主要病原体。广泛的生化和分子生物学工作已经鉴定出一种可诱导这些抗菌和免疫调节肽的核仁梭菌外膜蛋白。我们将这种蛋白称为fad - 1，即梭杆菌相关防御素诱导剂。此外，初步的横断面数据表明，婴儿唾液hBD水平明显低于老年群体。我们怀疑，与hBD诱导相关的年龄，可能还有其他上皮细胞来源的抗菌肽（amp），与表达fad - 1的核胞梭菌菌株的定植和持久性有关。显然，我们需要通过(1)开展流行病学研究，调查跨年龄谱的AMP水平，以建立总体、年龄分层和fad - 1相关分布；(2)确定fad - 1对amp的诱导特性及其对NHOEC保护的后续贡献；(3)通过分子和生化方法进一步表征fad - 1的功能，以确定hBD诱导的初步结构-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与宿主的共生策略，就像fad - 1一样，我们可能有一天能够利用这些策略来保护易感的粘膜部位。fad - 1是一项值得研究的新发现，它或其衍生物可能为药物设计提供一个新的方向，可以在局部利用以增强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.