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.

摘要 这项建议解决了基于干扰素(干扰素)的口腔粘膜屏障抗病毒反应的性质，以及 影响其疗效的细菌因素。干扰素是一种抗病毒细胞因子，在限制所有方面都是至关重要的 病毒感染的可能性。我们发现，III型干扰素或干扰素lambdas(干扰素-λS)优先通过口头表达 上皮细胞和干扰素-λ相关信号在口腔给予强大的、广谱的抗病毒免疫 粘膜屏障。屏障部位的细菌定殖体有可能调节宿主对病毒的易感性 感染。与此相一致，我们发现牙龈卟啉单胞菌(Pg)与口腔 生物失调和牙周病，特别地和完全抑制了干扰素信号的所有方面 病毒激动剂。这项研究的总体目标是表征PG诱导的干扰素-λ抑制对血管内皮细胞的影响。 病毒清除和中性粒细胞功能，以及确定干扰素-λ抑制PG的相关性 殖民主义。我们的主要假设是，干扰素-λ优先在口腔粘膜屏障诱导，并赋予 抗病毒免疫保护，不会引起炎症。此外，我们假设PG使两者脱离接触 动态平衡和可诱导的干扰素-λ反应，从而增加宿主对口腔病毒感染的易感性和 慢性炎症，也是PG持续存在的原因。这些假设将在以下方面得到验证 明确的目标。目的1：研究PG介导的干扰素-λ信号抑制对病毒清除的影响 在活体内。目的2：确定干扰素-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害和持续性炎症。目的：确定干扰素失活的作用 感染期间PG持续存在的信号转导。这项研究将提供基本的新奇信息，关于 PG在抑制口腔粘膜屏障抗微生物炎症反应中的作用。此外，一个 增加对口腔中提供抗病毒抵抗力的因素的了解具有非常重要的意义 包括SARS-Cov2在内的大量病毒可以感染口腔组织，引起局部和全身疾病。