Mechanisms of Immune Dysfunction in Oral Post-Acute Sequelae of Covid-19

Covid-19口腔急性后遗症中免疫功能障碍的机制

• 批准号: 10892624
• 负责人: Afsar Raza Naqvi
• 金额: $ 58.1万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-13 至 2024-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10892624
• 关键词: 2019-nCoV; ACE2; Actinobacillus actinomycetemcomitans; Adherence; Affect; Anti-Bacterial Agents; Attenuated; Bacteria; Biological Response Modifiers; Biopsy; Black Populations; Black race; COVID-19; COVID-19 risk; COVID-19 susceptibility; COVID-19 vaccination; Cells; Chronic; Clinical; Clinical Research; Cytomegalovirus; Data Set; Deposition; Epithelial Cells; Exhibits; Forsythia; Gingiva; Gingival Crevicular Fluid; Health; Herpesviridae; Hispanic; Hispanic Populations; Hospitalization; Human; Human Herpesvirus 4; Human body; Immune; Immune System Diseases; Immune response; Immunity; Immunologic Surveillance; Immunologics; Immunologist; Impairment; In Vitro; Infection; Inflammation; Inflammatory Infiltrate; Innate Immune Response; Knowledge; Lymphoid; Mediating; Metalloproteases; Microbe; Minority Groups; Modeling; Molecular; Mouth Diseases; Mucosal Immunity; Myelogenous; Not Hispanic or Latino; Open Reading Frames; Oral; Oral Examination; Oral Pathology; Oral health; Oral mucous membrane structure; Organ; Outcome; Outcome Study; Pathway interactions; Peptide Hydrolases; Periodontal Diseases; Periodontitis; Population; Porphyromonas gingivalis; Post-Acute Sequelae of SARS-CoV-2 Infection; Prevalence; Prospective cohort; Public Health; Recording of previous events; Regulatory T-Lymphocyte; Risk; Risk Factors; Role; SARS-CoV-2 infection; Saliva; Salvia; Scientist; Signal Transduction; Signs and Symptoms; Surface; Tooth structure; Tropism; Vaccinated; Vaccination; Vaccinee; Viral; Virion; Virulence Factors; Virus; Virus Diseases; Virus Replication; Work; Zoonoses; anergy; cohort; comparative; coronavirus disease; ds-DNA; exhaustion; health data; high risk population; immune activation; improved; inflammatory marker; inhibitor; keratinocyte; leukotoxin; new therapeutic target; novel; oral condition; oral immunity; oral tissue; pathogen; periodontopathogen; periopathogen; pre-pandemic; racial disparity; racial health disparity; receptor; receptor expression; screening; synergism; underserved community; unvaccinated

Abstract Coronavirus disease 2019 (Covid-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infecting non-vaccinated and vaccinated people. Covid-19 clinically affects multiple organs including oral mucosa where SARS-CoV-2 replication occurs to deposit virion into saliva in sufficient copies (>1000) to be detected. Public health data reveals Covid-19 and periodontitis disproportionally affects Non-Hispanic Blacks (NHB) and Hispanics (H). We hypothesize that periodontal disease (PD) pre- conditions oral mucosa for persistent oral pathology and oral Post-Acute Sequelae of Covid-19 (PASC). However, the cellular and molecular mechanisms underlying this relationship between Covid-19 and poor oral health outcomes are unclear. Extending our preliminary dataset of oral examination, and immune assessment of Black and Hispanic cohort, our Aim 1 involves a comparative analysis of the impact of vaccination on oral PASC indicators and perturbation in oral immune surveillance. We assessed this relationship before vaccination was available, which provides an opportunity to compare how periodontal health, Covid-19 infection, and the vaccination status affects minority population (NHB/H) versus Non-Hispanic White (NHW) with similar variables and risk for oral PASC. Saliva and gingival crevicular fluid (GCF) will be examined to perform comprehensive profiling of immune cells (both myeloid and lymphoid compartments) and assess mediators of immune cell activation, polarization and exhaustion contributing to impaired oral immunity. We will decipher three important gaps of knowledge in an underserved cohort: (1) whether infectivity of SARS-CoV-2 is affected by poor oral health?, (2) does Covid-19-induced inflammation worsen pre-existing periodontal health, and (3) does Covid-19 vaccination lessen oral PASC viz. periodontal inflammation? In Aim 2, we will examine whether previous intracellular periopathogens enhance risk for continual reinfection of SARS-CoV-2 and promote oral PASC. Our lab has optimized an in vitro infection model of SARS-CoV-2 in primary gingival epithelial cells (GEC) to dissect the role of periodontal pathogens (both bacteria and herpesviruses) enhancing viral tropism and replication. Characterizing periodontal microbe-SARS-CoV-2 interaction will unravel novel mechanisms that can be targeted to mitigate oral PASC. Our findings will support that periodontal pathogens increase host susceptibility to SARS- CoV-2 infection by providing a conducive microenvironment for viral tropism, and persistence. Next, we will decipher SARS-CoV-2-mediated mechanisms of impairing periodontal immunity. To this end, we will characterize the novel role of SARS-CoV-2- open reading frames (ORFs) in modulating oral antiviral and antibacterial immunity by examining viral entry and replication, expression of Pathogen Recognition Receptor (PRR) and downstream signaling activation. Successful outcomes of this study will disclose novel relationships between Covid-19 and PD as well as intracellular periodontal bacteria and viruses viz., SARS-CoV-2 and herpesviruses. Identification of pathogenic factors that promote SARS-CoV-2 oral tropism could serve as novel therapeutic targets to suppress oral PASC signs and symptoms.

抽象的 2019 年冠状病毒病（Covid-19）是一种由严重急性呼吸系统综合症引起的病毒感染 冠状病毒 2 (SARS-CoV-2)，感染未接种疫苗和接种疫苗的人。 Covid-19 的临床影响 包括口腔粘膜在内的多个器官，其中 SARS-CoV-2 发生复制，将病毒颗粒沉积到唾液中 检测到足够的副本（>1000）。公共卫生数据显示 Covid-19 与牙周炎的比例不成比例 影响非西班牙裔黑人 (NHB) 和西班牙裔 (H)。我们假设牙周病（PD）预先 改善口腔粘膜的持续性口腔病理和 Covid-19 口腔急性后遗症 (PASC)。 然而，Covid-19 与口腔不良之间这种关系背后的细胞和分子机制 健康结果尚不清楚。扩展我们的口腔检查和免疫评估的初步数据集 针对黑人和西班牙裔群体，我们的目标 1 涉及对疫苗接种对口腔的影响进行比较分析 PASC 指标和口腔免疫监测中的扰动。我们在接种疫苗之前评估了这种关系 可用，这提供了一个机会来比较牙周健康、Covid-19 感染和 疫苗接种状况对少数族裔 (NHB/H) 与非西班牙裔白人 (NHW) 的影响具有相似的变量 以及口服 PASC 的风险。将检查唾液和龈沟液（GCF）以进行全面检查 免疫细胞（骨髓和淋巴室）的分析并评估免疫细胞的介质 激活、极化和耗竭会导致口腔免疫力受损。我们将解读三个重要的 服务不足队列中的知识差距：(1) SARS-CoV-2 的传染性是否受到口腔不良的影响 健康？，(2) Covid-19 引起的炎症是否会恶化已有的牙周健康，以及 (3) Covid-19 是否会恶化 疫苗接种可减少口服 PASC，即。牙周炎症？在目标 2 中，我们将检查之前是否 细胞内周围病原体会增加 SARS-CoV-2 持续再感染的风险并促进口腔 PASC。我们的 实验室优化了原代牙龈上皮细胞（GEC）中 SARS-CoV-2 的体外感染模型来剖析 牙周病原体（细菌和疱疹病毒）增强病毒趋向性和复制的作用。 表征牙周微生物-SARS-CoV-2 相互作用将揭示可靶向的新机制 减轻口服 PASC。我们的研究结果将支持牙周病原体增加宿主对 SARS 的易感性 通过为病毒趋向性和持久性提供有利的微环境来抑制 CoV-2 感染。接下来，我们将 破译 SARS-CoV-2 介导的损害牙周免疫的机制。为此，我们将 描述了 SARS-CoV-2 开放阅读框（ORF）在调节口服抗病毒药物和药物中的新作用 通过检查病毒进入和复制、病原体识别受体的表达来实现抗菌免疫 (PRR) 和下游信号激活。这项研究的成功结果将揭示新的关系 Covid-19 和 PD 之间以及细胞内牙周细菌和病毒，即 SARS-CoV-2 和 疱疹病毒。促进 SARS-CoV-2 口腔向性的致病因素的鉴定可以作为新的方法 治疗目标是抑制口腔 PASC 体征和症状。