Regulation and Manipulation of Oral Type III Interferon Responses by Porphyromonas gingivalis

牙龈卟啉单胞菌对口腔 III 型干扰素反应的调节和操纵

• 批准号: 10595198
• 负责人: Juhi Bagaitkar
• 金额: $ 43.12万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595198
• 关键词: 2019-nCoV; Address; Agonist; Anatomy; Antiviral Response; Antiviral resistance; Bacterial Infections; Cells; Chronic; Complex; Data; Distant; Epithelial Cells; Epithelium; Gene Expression; Genes; Gingiva; Goals; IRF1 gene; Immune; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferon Receptor; Interferon Suppression; Interferon Type I; Interferon Type II; Interferons; Localized Disease; Location; Mediating; Microbe; NF-kappa B; Nature; Oncogenic Viruses; Oral; Oral cavity; Oral mucous membrane structure; Oropharyngeal; Outcome; Paralysed; Pathogenicity; Patients; Peptide Hydrolases; Periodontal Diseases; Periodontitis; Play; Porphyromonas gingivalis; Predisposition; Production; Reactive Oxygen Species; Refractory; Regulation; Role; STAT1 gene; Signal Transduction; Site; Surface; Systemic disease; Testing; Tissues; Viral; Virulence Factors; Virus; Virus Diseases; airway epithelium; antimicrobial; antiviral drug development; antiviral immunity; autocrine; cytokine; desensitization; dysbiosis; gastrointestinal; genetic signature; gingipain; in vivo; insight; mouse model; neutrophil; novel; oral cavity epithelium; oral tissue; paracrine; promoter; receptor; receptor binding; recruit; reproductive; respiratory; respiratory virus; response; transcription factor; viral resistance

ABSTRACT This proposal addresses the nature of interferon (IFN)-based antiviral responses at the oral mucosal barrier, and the bacterial factors that impact their efficacy. IFNs are antiviral cytokines that are critical in limiting all aspects of viral infection. We found that Type III IFNs or IFN lambdas (IFN-λs) are preferentially expressed by oral epithelial cells, and IFN-λ-associated signaling confers robust, broad-spectrum, antiviral immunity at the oral mucosal barrier. Bacterial colonizers at barrier sites have the potential to modulate host susceptibility to viral infection. Consistent with this, we found that Porphyromonas gingivalis (Pg), which is associated with oral dysbiosis and periodontal disease, singularly and totally dampened all aspects of IFN signaling in response to viral agonists. The overall goal of this study is to characterize the effect of Pg-induced IFN-λ suppression on viral clearance and neutrophil function, as well as determine the relevance of IFN-λ suppression for Pg colonization. Our main hypothesis is that IFN-λ is preferentially induced at the oral mucosal barrier and confers antiviral immune protection without inducing inflammation. Further, we hypothesize that Pg disengages both homeostatic and inducible IFN-λ responses, thereby enhancing host susceptibility to oral viral infection and to chronic inflammation, as well as contributing to Pg persistence. These hypotheses will be tested in the following specific aims. Aim 1: Characterize the impact of Pg-mediated suppression of IFN-λ signaling on viral clearance in vivo. Aim 2: Determine the contribution of IFN-λ mediated regulation of neutrophil effector functions to tissue damage and persistent inflammation during oral viral infections. Aim3: Determine the role of inactivation of IFN signaling in Pg persistence during infection. This study will provide fundamental novel information on the role of Pg in the suppression of anti-microbial inflammatory responses at the oral mucosal barrier. Additionally, an increased understanding of the factors that provide antiviral resistance in the oral cavity is highly significant as a large number of viruses, including SARS-Cov2, can infect oral tissues and cause local and systemic disease.

抽象的 该提案解决了口腔粘膜屏障处基于干扰素（IFN）的抗病毒反应的性质，以及 影响其功效的细菌因素。干扰素是抗病毒细胞因子，在限制各个方面都至关重要 病毒感染。我们发现 III 型 IFN 或 IFN lambda (IFN-λ) 优先通过口服表达 上皮细胞和 IFN-λ 相关信号传导赋予口腔强大的广谱抗病毒免疫力 粘膜屏障。屏障位点的细菌定殖者有可能调节宿主对病毒的易感性 感染。与此相一致的是，我们发现牙龈卟啉单胞菌（Pg），它与口腔相关。 菌群失调和牙周病，单独且完全抑制了 IFN 信号传导的各个方面，以响应 病毒激动剂。本研究的总体目标是表征 Pg 诱导的 IFN-λ 抑制对 病毒清除和中性粒细胞功能，以及确定 IFN-λ 抑制与 Pg 的相关性 殖民化。我们的主要假设是 IFN-λ 优先在口腔粘膜屏障处诱导并赋予 抗病毒免疫保护而不诱发炎症。此外，我们假设 Pg 使两者都脱离 稳态和诱导型 IFN-λ 反应，从而增强宿主对口腔病毒感染和 慢性炎症，以及导致 Pg 持续存在。这些假设将在下面进行检验 具体目标。目标 1：表征 Pg 介导的 IFN-λ 信号传导抑制对病毒清除的影响 体内。目标 2：确定 IFN-λ 介导的中性粒细胞效应功能调节对组织的贡献 口腔病毒感染期间的损伤和持续炎症。目标3：确定IFN失活的作用 感染期间 Pg 持续存在的信号传导。这项研究将提供有关作用的基本新颖信息 Pg 抑制口腔粘膜屏障的抗菌炎症反应。另外，一个 增加对口腔中产生抗病毒耐药性的因素的了解具有非常重要的意义 包括SARS-Cov2在内的大量病毒可感染口腔组织并引起局部和全身疾病。