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 冠状病毒疾病2019（COVID-19）是由严重急性呼吸系统综合征引起的病毒感染 冠状病毒2（SARS-COV-2），感染未接种疫苗的人和接种疫苗的人。 COVID-19在临床上影响 多个器官包括口服粘膜，其中发生了SARS-COV-2复制以将病毒体沉积到唾液中 要检测到足够的副本（> 1000）。公共卫生数据揭示了Covid-19和牙周炎不成比例 影响非西班牙裔黑人（NHB）和西班牙裔（H）。我们假设牙周疾病（PD）前 病态的口服粘膜，可用于持续的口腔病理学和COVID-19（PASC）的口服后遗症。 然而，19与口服不良之间关系的细胞和分子机制 健康结果尚不清楚。扩展我们的口试初步数据集和免疫评估 黑色和西班牙裔队列的目的1涉及对疫苗接种影响口服的影响的比较分析 PASC指标和口腔免疫监视的扰动。我们在疫苗接种之前评估了这种关系 可用，这提供了一个机会，可以比较牙周健康，Covid-19感染和 疫苗接种状况影响少数族裔人口（NHB/H）与非西班牙裔白人（NHW）相似的变量 和口服PASC的风险。将检查唾液和牙龈缝隙液（GCF）以进行全面 免疫细胞（髓样和淋巴室）的分析并评估免疫细胞的介质 激活，极化和精疲力尽，导致口服免疫力受损。我们将破译三个重要的 在服务不足的队列中的知识差距：（1）SARS-COV-2的感染力是否受到口服不良的影响 健康？（2）COVID-19引起的炎症是否恶化了牙周健康状况，（3）Covid-19 疫苗接种减少口服PASC。牙周炎症？在AIM 2中，我们将检查是否以前 细胞内围栏剂增加了持续再感染SARS-COV-2并促进口服PASC的风险。我们的 实验室优化了原代牙龈上皮细胞（GEC）中SARS-COV-2的体外感染模型以剖析 牙周病原体（细菌和疱疹病毒）的作用增强了病毒性的特性和复制。 表征牙周微生物-SARS-COV-2相互作用将揭示可以针对的新机制 减轻口服PASC。我们的发现将支持牙周病原体增加宿主对SARS的敏感性 - COV-2通过提供有利的微环境，以进行病毒性疗法和持久性。接下来，我们会的 破译SARS-COV-2介导的牙周免疫的机制。为此，我们将 表征SARS-COV-2-开放式阅读框（ORF）在调节口服抗病毒和 通过检查病毒入口和复制，病原体识别受体的表达，抗菌免疫力 （PRR）和下游信号传导激活。这项研究的成功结果将披露新的关系 在Covid-19和PD以及细胞内牙周细菌和病毒之间，即SARS-COV-2和 疱疹病毒。鉴定促进SARS-COV-2口腔tropismism的致病因素可以用作新颖 抑制口服PASC体征和症状的治疗靶标。