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 该建议涉及干扰素（IFN）基于口腔粘膜屏障的抗病毒反应的性质，以及 影响其效率的细菌工厂。 IFN是抗病毒细胞因子，对于限制所有方面至关重要 病毒感染。我们发现III型IFN或IFN lambdas（IFN-λs）优选通过口头表达 上皮细胞和IFN-λ相关信号供应口服的稳健，宽光谱，抗病毒免疫力 粘膜屏障。屏障部位的细菌殖民者有可能调节宿主对病毒的敏感性 感染。与此相一致，我们发现与口服有关 营养不良和牙周疾病，完全且完全诅咒IFN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IFN-λ抑制对 病毒清除率和中性粒细胞功能，并确定IFN-λ抑制与Pg的相关性 殖民化。我们的主要假设是，在口腔粘膜屏障上优选诱导IFN-λ并承认 没有诱导注射的抗病毒免疫保护。此外，我们假设PG脱离了两者 稳态和可诱导的IFN-λ反应，从而增强了宿主对口腔病毒感染的敏感性和对 慢性炎症，并导致PG持久性。这些假设将在以下测试 具体目标。 AIM 1：表征PG介导的IFN-λ信号抑制对病毒清除的影响 体内。 AIM 2：确定IFN-λ介导的中性粒细胞效应功能对组织的贡献 口腔病毒感染期间的损害和持续感染。 AIM3：确定IFN失活的作用 感染过程中PG持久性的信号传导。这项研究将提供有关作用的基本新信息 PG在抑制口腔粘膜屏障的抗微生物炎症反应中。另外， 人们对口腔中提供抗病毒抗性的因素的了解非常重要，因为 包括SARS-COV2在内的大量病毒会感染口腔组织并引起局部和全身性疾病。