Lung inflammation and type I interferons in Bordetella pertussis infection

百日咳杆菌会导致长时间的剧烈咳嗽，并使婴儿面临致命疾病的风险。由于疫苗无效、细菌菌株进化以及对发病机制知之甚少，美国的百日咳病例达到了60年来的最高水平。为了对抗这一点，必须开发宿主靶向疗法来有效地治疗患者。RNAseq转录分析确定I型干扰素受体亚单位IFNAR1是百日咳杆菌感染小鼠肺部基因表达的唯一最重要的上游激活因子。提示I型干扰素信号在百日咳发病机制和疾病发生中起重要作用。I型干扰素被经典地认为是主要的抗病毒细胞因子，然而，它们也参与了几种细菌感染模型的炎症和发病机制。I型干扰素在百日咳杆菌中的作用是一个研究较少的领域。最近发表的一项研究发现，在感染百日咳杆菌的小鼠肺中，产生干扰素α的浆细胞样树突状细胞显著上调。这些数据与初步数据一起表明，I型干扰素水平和促炎细胞因子基因表达之间存在明显的关联，表明这些经典的抗病毒细胞因子可能在加重百日咳炎症病理和疾病方面发挥作用。在百日咳杆菌感染期间，将使用没有IFNAR1受体或具有不能下调的IFNAR1受体改变的转基因小鼠来研究I型干扰素受体信号在百日咳杆菌感染期间肺部炎症病理中的作用。此外，还将研究在百日咳杆菌感染过程中参与这一信号转导的特定细胞类型，以及TLR9信号在诱导I型干扰素中的作用。这项研究的结果将阐明I型干扰素在百日咳杆菌感染和疾病中的作用，并为未来百日咳和可能的其他呼吸道感染的治疗试验提供潜在的宿主靶点。

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.