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 该提案解决了在口腔粘膜屏障处基于干扰素（IFN）的抗病毒应答的性质， 影响其功效的细菌因素。干扰素是抗病毒细胞因子，在限制所有方面都至关重要 病毒感染。我们发现，III型IFN或IFN-λ s（IFN-λs）优先表达于口腔粘膜， 上皮细胞和IFN-λ相关信号传导在口腔中赋予强大的，广谱的抗病毒免疫力。 粘膜屏障屏障部位的细菌定殖者有可能调节宿主对病毒的易感性 感染与此一致，我们发现牙龈卟啉单胞菌（Pg），这是与口腔 菌群失调和牙周病，单独和完全抑制干扰素信号的所有方面，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IFN-γ表达的影响。 病毒清除和中性粒细胞功能，以及确定IFN-λ抑制与Pg 殖民化我们的主要假设是IFN-λ优先在口腔粘膜屏障被诱导， 抗病毒免疫保护而不诱导炎症。此外，我们假设PG使两者都脱离 稳态和诱导型IFN-λ应答，从而增强宿主对口腔病毒感染的易感性， 慢性炎症，以及有助于Pg持久性。这些假设将在下面进行检验 具体目标。目的1：表征Pg介导的IFN-λ信号转导抑制对病毒清除的影响 in vivo.目的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。目的3：确定IFN灭活的作用 感染期间Pg持续存在的信号传导。这项研究将提供关于以下作用的基本新信息： 前列腺素抑制口腔黏膜屏障抗微生物炎症反应。此外， 增加对口腔中提供抗病毒耐药性的因素的理解， 包括SARS-Cov 2在内的大量病毒可感染口腔组织并引起局部和全身性疾病。