Lung inflammation and type I interferons in Bordetella pertussis infection

百日咳博德特氏菌感染中的肺部炎症和 I 型干扰素

• 批准号: 9768877
• 负责人: Jeremy Gordon Ardanuy
• 金额: $ 3.83万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768877
• 关键词: Address; Affect; Antibiotic Therapy; Antiviral Agents; Area; Autocrine Communication; Bacterial DNA; Bacterial Infections; Blocking Antibodies; Bone Marrow; Bordetella pertussis; Cell Culture Techniques; Cells; Clinical; Coughing; Cytokine Gene; DNA; Data; Dendritic Cells; Development; Disease; Down-Regulation; Evolution; Future; G Protein-Coupled Receptor Signaling; Gene Expression; Genetically Engineered Mouse; Goals; IFNAR1 gene; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Integration Host Factors; Interferon Receptor; Interferon Type I; Interferon-alpha; Interferons; Intervention; Lung; Lung Inflammation; Modeling; Mus; Myeloid Cells; Outcomes Research; Paracrine Communication; Pathogenesis; Pathology; Patients; Pattern recognition receptor; Pertussis; Pertussis Toxin; Play; Production; Publishing; Receptor Signaling; Reporting; Respiratory Tract Infections; Risk; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; United States; Up-Regulation; Vaccines; Virulence Factors; cell type; combat; cytokine; experimental study; insight; macrophage; monocyte; new therapeutic target; prevent; receptor; response; targeted treatment; therapeutic evaluation; transcriptome sequencing; transcriptomics; type I interferon receptor

Bordetella pertussis causes prolonged severe cough and puts infants at risk of fatal disease. Cases of pertussis are at a 60 year high in the United States due to a combination of an ineffective vaccine, bacterial strain evolution, and a poorly understood mechanism of pathogenesis. To combat this, host targeted therapeutics must be developed to effectively treat patients. An RNAseq transcriptomic analysis identified type I interferon (IFN) receptor subunit, IFNAR1, as the single most significant upstream activator of gene expression in the lungs of B. pertussis-­infected mice. This suggests that type I IFN signaling plays a crucial role in pertussis pathogenesis and disease. Type I IFNs are classically considered the major antiviral cytokine class, however, they are also involved in inflammation and pathogenesis of several bacterial infection models. The role of type I IFNs in B. pertussis is an understudied area. Recently, a study was published in which IFNα-­producing plasmacytoid dendritic cells were found to be significantly upregulated in the lungs of B. pertussis-­infected mice. These data, in tandem with preliminary data that show a clear association between type I IFN levels and proinflammatory cytokine gene expression, indicate that these classically antiviral cytokines may function to exacerbate pertussis inflammatory pathology and disease. The role of type I IFN receptor signaling in lung inflammatory pathology during B. pertussis infection will be studied using genetically modified mice that either have no IFNAR1 receptor or have an altered IFNAR1 receptor that cannot be downregulated. Additionally, specific cell types involved in this signaling during B. pertussis infection and the role of TLR9 signaling in type I IFN induction will be investigated. The outcome of this research will elucidate the role of type I IFNs in B. pertussis infection and disease and provide a potential host target for future therapeutic testing in pertussis and possibly other respiratory infections.

百日咳杆菌会引起长时间的剧烈咳嗽，使婴儿有患致命疾病的危险。在美国，百日咳病例处于60年来的最高水平，这是由于疫苗无效、细菌菌株进化和对发病机制知之甚少的综合作用。为了解决这一问题，必须开发宿主靶向疗法以有效治疗患者。RNAseq转录组学分析鉴定I型干扰素（IFN）受体亚基IFNAR 1是B肺中基因表达的单一最重要上游激活剂。百日咳杆菌感染的小鼠。这表明I型IFN信号在百日咳发病机制和疾病中起着至关重要的作用。I型IFN被经典地认为是主要的抗病毒细胞因子类别，然而，它们也参与几种细菌感染模型的炎症和发病机制。I型干扰素在B.百日咳是一个研究不足的领域。最近，发表了一项研究，其中发现产生IFNα-γ的浆细胞样树突细胞在B的肺中显著上调。百日咳杆菌感染的小鼠。这些数据，在串联的初步数据，显示I型IFN水平和促炎细胞因子基因表达之间的明确关联，表明这些经典的抗病毒细胞因子可能起到加剧百日咳炎性病理和疾病。I型IFN受体信号在B肺炎症病理中的作用。百日咳感染将使用基因修饰的小鼠进行研究，这些小鼠或者没有IFNAR 1受体，或者具有不能下调的改变的IFNAR 1受体。此外，在B.将研究百日咳感染和TLR 9信号传导在I型IFN诱导中的作用。本研究的结果将阐明I型IFN在B中的作用。百日咳感染和疾病，并为百日咳和可能的其他呼吸道感染的未来治疗测试提供潜在的宿主靶标。