Ontogeny Of Oral Epithelial Antimicrobial Peptides

描述(由申请人提供)：先天免疫系统，一种进化上古老的反应，被认为在出生时或生命的最初几天就存在并具有功能。然而，共生细菌在“启动”先天免疫中扮演的角色，即调节其反应，以及在生命的哪个个体发生时开始发生，尚不清楚。我们实验室的最新发现使我们推测，口腔先天性免疫反应的个体发育可能与口腔中的生物定植有关。我们最近发现，核梭杆菌是一种普遍存在于人类口腔中的革兰氏阴性细菌，它能诱导正常口腔上皮细胞表达人β防御素-2(hBD-2)和hBD-3，从而对牙周破坏的主要病原菌牙龈卟啉单胞菌的侵袭具有保护作用。广泛的生化和分子生物学研究已经鉴定出一种核盘藻外膜蛋白，它可以诱导这些抗菌肽和免疫调节肽。我们将该蛋白称为FAD-I，即梭杆菌相关防御素诱导剂。此外，初步的横断面数据表明，婴儿时期的唾液HBD水平显著低于老年人群。我们怀疑，与HBD诱导相关的年龄相关，可能还有其他上皮细胞衍生的抗菌肽(AMPs)，与表达FAD-I的核杆菌菌株的定植和持久性相关。显然，我们需要通过以下方式更多地了解这种动态：(1)进行流行病学研究，以调查AMP在整个年龄段的水平，以建立总体的、年龄分层的和FAD-I相关的分布；(2)确定FAD-I对AMP的诱导特性及其随后对NHOEC保护的贡献；以及(3)通过采用分子和生化方法进一步表征FAD-I的功能，以确定HBD诱导中的初步结构-功能关系。通过更好地了解个体先天性免疫AMP谱的个体发生谱，我们可能能够识别出易受粘膜感染的个体。通过发现潜在的与宿主有益的共生策略，就像FAD-I所显示的那样，我们有朝一日可能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，有必要调查它或其衍生物可能为药物设计提供新方向的可能性，这种新方向可能被当地利用来增强大自然自身的防御能力。

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.