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，可以影响高达90%的世界人口。临床和基础研究表明，口腔螺旋体齿垢密螺旋体（Treponema denticola，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、口面脓肿和根尖周射线可透性。已有研究表明Td能诱导人牙龈上皮细胞和牙龈成纤维细胞的肌动蛋白重排和脱落。然而，尚未确定相应的毒力因子。封闭小带毒素（Zot）最初在霍乱弧菌中发现。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推定的Zot样毒素（TDE 0298）;进一步的研究表明，这种推定的毒素能够诱导人牙龈成纤维细胞的细胞骨架重排。基于这些数据，我们假设TDE 0298是一种Zot样毒素，可能通过调节人牙龈细胞中的细胞骨架成分来促进Td的组织侵袭性和毒力。为了验证这一假设，拟议的研究将集中在以下具体目的：目的1#：确定TDE 0298是否具有与霍乱弧菌Zot相似的毒性特征;目的2#：研究TDE 0298诱导肌动蛋白重组的分子机制;目的3#：确定TDE 0298在Td体外和体内毒力中的作用。Zot样毒素在任何口腔病原体中都没有报道。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，以及它在Td发病机制中的作用。这些目标的实现可能最终导致牙周感染预防和治疗的新方法。 公共卫生相关性：牙周病可以影响高达90%的世界人口，这主要是由多种微生物感染引起的。口腔螺旋体齿垢密螺旋体与人类牙周和牙髓疾病密切相关。本研究的目的是探讨一种假定的Zot样毒素在T。齿垢

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.