Role of Zonula Occludens Toxin in the Pathogenesis of Treponema denticola

描述（申请人提供）：牙周病是一组影响牙齿周围结构的感染，主要包括牙龈炎和牙周炎。牙周病最常见的形式是牙龈炎，这是非常普遍的，可影响高达90%的世界人口。临床和基础研究都表明，口腔螺旋体牙密螺旋体（Td）与人类牙周和牙髓疾病密切相关，如急性坏死性溃疡性牙龈炎、早发性和慢性牙周炎、口面脓肿和根尖周放射性。先前的研究表明，Td能够诱导人上皮细胞和牙龈成纤维细胞的肌动蛋白重排和脱离。然而，相应的毒力因素尚未确定。闭塞小带毒素（Zot）最初是在霍乱弧菌中发现的。这种毒素能够通过影响细胞间紧密连接的结构来增加小肠的通透性。在初步研究中，在Td的基因组中发现了一种假定的zot样毒素（TDE0298）；进一步的研究表明，这种假定的毒素能够诱导人类牙龈成纤维细胞的细胞骨架重排。基于这些数据，我们假设TDE0298是一种zot样毒素，可能通过调节人类牙龈细胞的细胞骨架成分来促进Td的组织侵袭性和毒性。为了验证这一假设，拟议的研究将集中在以下具体目标上：目标1#：确定TDE0298是否具有与霍乱弧菌Zot相似的毒性特征；目的2#：探讨TDE0298诱导肌动蛋白重组的分子机制；目的3#：确定TDE0298在体外和体内对Td毒力的作用。带状疱疹样毒素尚未在任何口腔病原体中发现。这些研究将有助于我们了解该毒素的细胞毒性及其作用的潜在分子机制，以及其在Td发病机制中的作用。所提出的目标的实现可能最终导致预防和治疗牙周感染的新手段。

DESCRIPTION (provided by applicant): Periodontal diseases are a group of infections that affect the structures surrounding teeth, mainly including gingivitis and periodontitis. The most common form of periodontal diseases is gingivitis, which is highly prevalent and can affect up to 90% of the worldwide population. Both clinical and basic studies have shown that the oral spirochete Treponema denticola (Td) is strongly associated with human periodontal and endodontic diseases, such as acute necrotizing ulcerative gingivitis, early-onset and chronic periodontitis, orofacial abscesses, and periapical radiolucencies. Previous studies have shown that Td is able to induce the actin rearrangement and detachment of human epithelial cells and gingival fibroblasts. However, the corresponding virulent factor(s) has not yet been identified. Zonula occludens toxin (Zot) was originally identified in Vibrio cholerae. This toxin is able to increase the permeability of the small intestine by affecting the structure of the intercellular tight junctions. In preliminary studies, a putative Zot-like toxin (TDE0298) was found in the genome of Td; and further studies have shown that this putative toxin is able to induce the cytoskeletal rearrangement of human gingival fibroblasts. Based on these data, we hypothesize that TDE0298 is a Zot-like toxin that may contribute to the tissue invasiveness and virulence of Td by modulating cytoskeletal components in human gingival cells. To test this hypothesis, the proposed studies will focus on the following specific aims: Aim 1#: To determine if TDE0298 possesses toxic characteristics similar to V. cholerae Zot; Aim 2#: To investigate the molecular mechanism of the actin reorganization induced by TDE0298; Aim 3#: To determine the role of TDE0298 in the virulence of Td in vitro and in vivo. Zot-like toxin has not been reported in any oral pathogens. The proposed studies will help us to understand the cytotoxicity of this toxin and the potential molecular mechanism involved in its action, as well as its role in the pathogenesis of Td. The achievement of the proposed goals may eventually lead to new means of prevention and treatment for periodontal infections. PUBLIC HEALTH RELEVANCE: Periodontal diseases can affect up to 90% of the worldwide population, which are primarily caused by polymicrobial infections. Oral spirochete Treponema denticola is strongly associated with human periodontal and endodontic diseases. The goal of this proposal is to investigate the role of a putative Zot-like toxin in the pathogenesis of T. denticola.