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

I 型干扰素在百日咳博德特氏菌发病机制中的年龄依赖性作用

• 批准号: 9788241
• 负责人: NICHOLAS H CARBONETTI
• 金额: $ 38.63万
• 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: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788241
• 关键词: Address; Adult; Affect; Age; Animal Model; Antibiotic Therapy; Antiviral Agents; Attenuated; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Bacterial Infections; Bordetella pertussis; Cell Culture Techniques; Cells; Child; Clinical Trials; Communicable Diseases; Coughing; Country; DNA; Data; Dendritic Cells; Dependence; Development; Disease; Disease model; Dose; Down-Regulation; Drug Receptors; Endocytosis; Epidemic; Gene Expression; Genes; Human; IFNAR1 gene; Immune response; Immunosuppressive Agents; Individual; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferon Receptor; Interferon Type I; Interferons; Interleukin-10; Intranasal Administration; Lead; Ligands; Lung; Lung Inflammation; Mediating; Modeling; Mus; Pathogenesis; Pathology; Pathway interactions; Pattern recognition receptor; Pertussis; Pertussis Vaccine; Pharmaceutical Preparations; Phase; Play; Public Health; Publishing; Receptor Signaling; Relapsing-Remitting Multiple Sclerosis; Role; STAT1 gene; Signal Transduction; Sphingosine-1-Phosphate Receptor; TLR9 gene; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Vaccination; Vaccines; age related; cytokine; differential expression; effective therapy; novel; novel therapeutics; protective effect; response; targeted treatment; transcriptome sequencing; transcriptomics; type I interferon receptor

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.

项目概要   最近细菌性疾病百日咳的发病率达到了 60 年来的最高水平。 目前使用的无细胞百日咳疫苗不足，并且没有有效的治疗方法 由于抗生素治疗无效，因此我们仍然需要针对宿主的治疗。 对百日咳的发病机制了解甚少，因此尚不清楚其宿主是哪一种 通过RNAseq转录组学分析，我们发现适合治疗干预的目标。 I型干扰素（IFN）受体亚基IFNAR1是小鼠最重要的上游激活剂 响应百日咳博德特氏菌感染而差异表达的肺部基因是关键。 细胞因子在免疫反应和抗病毒防御中发挥作用，但它们也会加剧炎症和 多种疾病模型的发病机制 I 型干扰素对多种细菌有不同的影响。 我们的初步数据表明，对某些人有保护作用，但对另一些人有害。 I 型干扰素的表达在百日咳博德特氏菌感染的成年小鼠的肺部表达上调，并且它们 然而，在幼年小鼠中，百日咳的发病机制加剧。 与成年小鼠（如人类）明显不同，我们的初步数据表明 I 型 IFN 信号传导对百日咳博德特氏菌疾病具有保护作用，表明 I 型 IFN 效应具有年龄依赖性。 我们还一直在研究1-磷酸鞘氨醇（S1P）受体配体作为候选宿主- S1P 受体配体药物 FTY720 在人类中用作百日咳靶向治疗药物。 治疗复发缓解型多发性硬化症，其他类似药物正在进行各种临床试验 炎症性疾病，在已发表的研究中证明了这些药物的转化潜力。 发现对百日咳博德特氏菌感染的成年小鼠施用单剂量的 S1P 受体配体 此外，我们的初步数据表明 S1P 显着减少了肺部炎症病理。 受体配体治疗通过下调感染成人的 I 型 IFN 信号传导来减轻炎症 小鼠，与 I 型干扰素恶化肺部炎症病理学的假设一致。 因此，本提案的目的是检验以下假设：(i) I 型干扰素有助于 成年小鼠的肺部炎症病理学和百日咳博德特氏菌病的发病机制，但在 幼年小鼠，以及 (ii) S1P 受体药物可减轻百日咳博德特氏菌感染的肺部炎症病理 我们将使用小鼠感染和抑制 I 型 IFN 受体信号传导的组合来治疗成年小鼠。 细胞培养研究来测试这些假设并研究机制，我们将利用 影响 I 型干扰素受体信号传导的基因改造小鼠 宿主靶标的识别和鉴定。 为患有使人衰弱甚至致命的百日咳的人开发治疗小说 将对这种疾病产生重大的公共卫生影响。