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.

摘要 2019冠状病毒病（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），感染未接种疫苗和接种疫苗的人。COVID-19临床影响 包括口腔粘膜在内的多个器官发生SARS-CoV-2复制，使病毒粒子存款到唾液中， 足够的拷贝数（>1000）。公共卫生数据显示，2019冠状病毒病和牙周炎 影响非西班牙裔黑人（NHB）和西班牙裔（H）。我们假设牙周病（PD）前- 口腔粘膜持续性病理和口腔急性后COVID-19后遗症（PASC）。 然而，COVID-19和口腔不良之间这种关系的细胞和分子机制， 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 在黑人和西班牙裔队列中，我们的目标1涉及疫苗接种对口腔免疫的影响的比较分析。 PASC指示剂和口服免疫监视中的扰动。我们在接种疫苗前评估了这种关系 提供了一个机会，比较牙周健康，Covid-19感染和 疫苗接种状态影响少数民族人群（NHB/H）与非西班牙裔白色人群（NHW），变量相似 和口服PASC的风险。唾液和龈沟液（GCF）将被检查，以进行全面的 分析免疫细胞（骨髓和淋巴区室）并评估免疫细胞介质 激活、极化和耗竭，导致口腔免疫受损。我们将破译三个重要的 缺乏服务的队列中的知识差距：（1）SARS-CoV-2的传染性是否受口腔不良的影响 健康？，(2)COVID-19引起的炎症是否会恶化先前存在的牙周健康，以及（3）COVID-19是否会 接种疫苗可减轻口腔PASC，即牙周炎？在目标2中，我们将检查以前是否 胞内周围病原体增加了SARS-CoV-2持续再感染风险，并促进了口服PASC。我们 实验室优化了SARS-CoV-2在原代牙龈上皮细胞（GEC）中的体外感染模型， 牙周病原体（细菌和疱疹病毒）增强病毒嗜性和复制的作用。 表征牙周微生物-SARS-CoV-2相互作用将揭示可以靶向的新机制 减轻口腔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- CoV-2感染通过为病毒嗜性和持久性提供有利的微环境。接下来我们就 破译SARS-CoV-2介导的损害牙周免疫的机制。为此我们将 表征SARS-CoV-2开放阅读框架（ORF）在调节口服抗病毒药物中的新作用， 通过检测病毒进入和复制、病原体识别受体表达的抗菌免疫 (PRR)和下游信号激活。这项研究的成功结果将揭示新的关系 以及细胞内牙周细菌和病毒，即，SARS-CoV-2和 疱疹病毒鉴定促进SARS-CoV-2口服嗜性的致病因子可以作为新的 治疗目标是抑制口腔PASC体征和症状。