Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago, Chile.
Centro de Investigación Clínica Avanzada (CICA), Hospital Clínico Universidad de Chile, Santiago, Chile.
Front Immunol. 2020 Nov 9;11:588036. doi: 10.3389/fimmu.2020.588036. eCollection 2020.
Periodontal disease is a disease of tooth-supporting tissues. It is a chronic disease with inflammatory nature and infectious etiology produced by a dysbiotic subgingival microbiota that colonizes the gingivodental sulcus. Among several periodontal bacteria, () highlights as a keystone pathogen. Previous reports have implied that chronic inflammatory response and measurable bone resorption are observed in young mice, even after a short period of periodontal infection with , which has been considered as a suitable model of experimental periodontitis. Also, encapsulated strains are more virulent than capsular-defective mutants, causing an increased immune response, augmented osteoclastic activity, and accrued alveolar bone resorption in these rodent experimental models of periodontitis. Recently, has been associated with Alzheimer's disease (AD) pathogenesis, either by worsening brain pathology in AD-transgenic mice or by inducing memory impairment and age-dependent neuroinflammation middle-aged wild type animals. We hypothesized here that the more virulent encapsulated strains could trigger the appearance of brain AD-markers, neuroinflammation, and cognitive decline even in young rats subjected to a short periodontal infection exposure, due to their higher capacity of activating brain inflammatory responses. To test this hypothesis, we periodontally inoculated 4-week-old male Sprague-Dawley rats with K1, K2, or K4 serotypes and the K1-isogenic non-encapsulated mutant (GPA), used as a control. 45-days after periodontal inoculations with serotypes, rat´s spatial memory was evaluated for six consecutive days in the Oasis maze task. Following functional testing, the animals were sacrificed, and various tissues were removed to analyze alveolar bone resorption, cytokine production, and detect AD-specific biomarkers. Strikingly, only K1 or K2 -infected rats displayed memory deficits, increased alveolar bone resorption, pro-inflammatory cytokine production, changes in astrocytic morphology, increased Aβ1-42 levels, and Tau hyperphosphorylation in the hippocampus. None of these effects were observed in rats infected with the non-encapsulated bacterial strains. Based on these results, we propose that the bacterial virulence factors constituted by capsular polysaccharides play a central role in activating innate immunity and inflammation in the AD-like pathology triggered by in young rats subjected to an acute experimental infection episode.
牙周病是一种牙齿支持组织疾病。它是一种慢性疾病，具有炎症性质和感染病因，由定植于龈沟的生态失调龈下微生物群引起。在几种牙周细菌中，()被认为是关键病原体。先前的报告表明，即使在牙周感染后的短时间内，年轻小鼠也会观察到慢性炎症反应和可测量的骨吸收，这被认为是实验性牙周炎的合适模型。此外，包膜()菌株比无包膜缺陷突变体更具毒力，导致这些啮齿动物实验性牙周炎模型中免疫反应增强、破骨细胞活性增强和牙槽骨吸收增加。最近，()与阿尔茨海默病 (AD) 的发病机制有关，要么通过加重 AD 转基因小鼠的脑病理学，要么通过诱导记忆障碍和与年龄相关的神经炎症。我们假设，由于其更高的激活大脑炎症反应的能力，更具毒力的包膜()菌株甚至可以在年轻大鼠中引发大脑 AD 标志物、神经炎症和认知能力下降的出现，即使它们在短时间的牙周感染暴露后。为了验证这一假设，我们用 K1、K2 或 K4 血清型和 K1 同源非包膜突变体 (GPA) 对 4 周龄雄性 Sprague-Dawley 大鼠进行牙周接种，并将 GPA 用作对照。在 K1 血清型牙周接种 45 天后，在绿洲迷宫任务中连续六天评估大鼠的空间记忆。功能测试后，处死动物，取出各种组织，分析牙槽骨吸收、细胞因子产生，并检测 AD 特异性生物标志物。令人惊讶的是，只有 K1 或 K2 感染的大鼠显示出记忆缺陷、牙槽骨吸收增加、促炎细胞因子产生增加、星形胶质细胞形态改变、Aβ1-42 水平升高和海马 Tau 过度磷酸化。在感染非包膜细菌株的大鼠中没有观察到这些影响。基于这些结果，我们提出，由荚膜多糖构成的细菌毒力因子在激活年轻大鼠急性实验性感染后由引起的 AD 样病理学中的固有免疫和炎症中起核心作用。
