Age-dependent role of type I interferon in Bordetella pertussis pathogenesis

项目总结 -- 最近，细菌性百日咳的发病率达到了60年来的最高水平。然而， 目前使用的无细胞百日咳疫苗是不够的，目前还没有有效的治疗方法。 百日咳。由于抗生素治疗无效，因此需要针对宿主的治疗方法。然而，我们仍然 对百日咳的发病机制了解很少，因此不清楚是哪种宿主 靶点适合进行治疗干预。通过RNAseq转录组学分析，我们发现 I型干扰素受体亚单位IFNAR1是小鼠最重要的上游激活剂 百日咳杆菌感染后肺组织差异表达基因的研究I型IFN是关键 免疫反应和抗病毒防御中的细胞因子，但它们也会加剧炎症和 发病机制涉及多种疾病模型。I型干扰素对多种细菌有不同的作用 感染，对一些人是保护的，对另一些人是有害的。我们的初步数据显示 在感染百日咳杆菌的成年小鼠肺中，I型IFN的表达上调，并且它们 加重肺部炎症病理。然而，在幼年小鼠中，百日咳的发病机制 与成年小鼠(如人类)显著不同，我们的初步数据表明，I型干扰素 信号对百日咳杆菌病有保护作用，表明I型干扰素的作用与年龄有关。 我们也一直在研究鞘氨醇-1-磷酸(S1P)受体配体作为候选宿主- 百日咳的靶向治疗。一种S1P受体配体药物FTY720在人类中用作 治疗复发-缓解型多发性硬化症的药物和其他类似药物正在进行各种临床试验 炎症性疾病，展示了这些药物的翻译潜力。在已发表的研究中，我们 发现给感染百日咳杆菌的成年小鼠单次注射S1P受体配体 明显减轻肺组织炎症病理改变。此外，我们的初步数据表明，S1P 受体配体治疗通过下调感染成人I型干扰素信号来减轻炎症 小鼠，与I型干扰素加重肺部炎症病理的假设一致。 因此，本提案的目的是检验(I)第一类IFN有助于 百日咳杆菌病成年小鼠的肺炎性病理和发病机制但具有保护性作用 幼鼠和(Ii)S1P受体药物减轻百日咳杆菌感染的肺部炎症病理 成年小鼠通过抑制I型干扰素受体信号。我们将结合使用老鼠感染和 细胞培养研究来验证这些假设并研究机制，我们将利用 影响I型干扰素受体信号的转基因小鼠。确定主机目标和 百日咳患者虚弱有时致命的新疗法的发展 将对这种疾病产生重大的公共卫生影响。

PROJECT SUMMARY   Recent levels of the bacterial disease pertussis are at their highest in 60 years. However, the currently used acellular pertussis vaccine is inadequate and no effective therapies exist for treatment of pertussis. Since antibiotic therapy is ineffective, host-targeted therapeutics are needed. However, we still have a very poor understanding of the pathogenesis of pertussis and therefore it is unclear which host targets are appropriate for therapeutic intervention. By RNAseq transcriptomics analysis, we found that the type I interferon (IFN) receptor subunit IFNAR1 was the most significant upstream activator of mouse lung genes differentially expressed in response to Bordetella pertussis infection. Type I IFNs are key cytokines in immune responses and antiviral defense, but they also exacerbate inflammation and pathogenesis in a variety of disease models. Type I IFNs have diverse effects on a variety of bacterial infections, being protective for some and deleterious for others. Our preliminary data indicate that expression of type I IFNs is upregulated in the lungs of B. pertussis-infected adult mice and that they exacerbate lung inflammatory pathology. However, in infant mice, in which the pathogenesis of pertussis is markedly different from that in adult mice (as in humans), our preliminary data suggest that type I IFN signaling is protective against B. pertussis disease, indicating age-dependence of type I IFN effects. We have also been studying sphingosine-1-phosphate (S1P) receptor ligands as candidate host- targeted therapeutics for pertussis. An S1P receptor ligand drug, FTY720, is used in humans as a therapy for relapsing-remitting multiple sclerosis, and other similar drugs are in clinical trials for various inflammatory disorders, demonstrating the translational potential of these drugs. In published studies, we found that administration of a single dose of S1P receptor ligands to B. pertussis-infected adult mice significantly reduced lung inflammatory pathology. Furthermore, our preliminary data suggest that S1P receptor ligand treatment reduces inflammation by downregulating type I IFN signaling in infected adult mice, consistent with the hypothesis that type I IFNs exacerbate lung inflammatory pathology. Therefore, the aims of this proposal are to test the hypotheses that (i) type I IFNs contribute to lung inflammatory pathology and pathogenesis of B. pertussis disease in adult mice but are protective in infant mice, and (ii) S1P receptor drugs attenuate lung inflammatory pathology in B. pertussis-infected adult mice by inhibiting type I IFN receptor signaling. We will use a combination of mouse infection and cell culture studies to test these hypotheses and investigate mechanisms, and we will take advantage of genetically altered mice that impact type I IFN receptor signaling. Identification of host targets and development of novel therapeutics for individuals suffering from debilitating and sometimes fatal pertussis will have a major public health impact on this disease.