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: 10241992
• 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/10241992
• 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; 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; Vaccination; Vaccines; age related; cytokine; differential expression; effective therapy; novel; novel therapeutics; protective effect; response; targeted treatment; therapeutically effective; 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.

项目摘要   最近的细菌病百日咳水平在60年来最高。但是， 目前使用的细胞百日咳疫苗不足，没有有效的疗法来治疗 百日咳。由于抗生素治疗无效，因此需要进行宿主靶向疗法。但是，我们仍然 对百日咳的发病机理有很差的了解，因此尚不清楚哪个宿主 目标适合治疗干预。通过RNASEQ转录组学分析，我们发现 I型I Interferon（IFN）受体亚基IFNAR1是小鼠最重要的上游激活因子 肺基因反应于百日咳的感染。 I类IFN是关键 免疫反应和抗病毒防御中的细胞因子，但它们也会加剧注射和 多种疾病模型中的发病机理。 I型IFN对各种细菌具有潜水员的影响 感染，受到某些人的保护，对其他人有害。我们的初步数据表明 I型IFN的表达在B.百日咳成年小鼠的肺中进行了更新，并且 恶化的肺部感染病理。然而，在婴儿小鼠中，百日咳发病机理 与成年小鼠（如人类一样）明显不同，我们的初步数据表明I型IFN 信号传导受到百日咳疾病的保护，表明I型IFN效应的年龄依赖性。 我们还一直在研究鞘氨醇1-磷酸（S1P）受体配体作为候选宿主 - 百日咳的靶向疗法。 S1P受体配体药物FTY720在人类中用作 用于复发的多发性硬化症和其他类似药物的治疗也在各种临床试验中 炎症性疾病，证明了这些药物的翻译潜力。在发表的研究中，我们 发现将单剂量的S1P受体配体给予百日咳芽孢杆菌感染的成年小鼠 大大降低了肺部炎症病理学。此外，我们的初步数据表明S1P 受体配体治疗通过下调感染的成年人的I型IFN信号来降低感染 小鼠，与I型IFNS加剧肺炎症病理学的假设一致。 因此，该提案的目的是检验（i）I型IFN有助于的假设 成年小鼠百日咳疾病的肺部炎症病理学和发病机理，但受到保护 婴儿小鼠和（ii）S1P受体药物减弱了芽孢杆菌感染的肺部感染病理 成年小鼠通过抑制I型IFN受体信号传导。我们将结合小鼠感染和 细胞培养研究以检验这些假设并研究机制，我们将利用 影响I型IFN受体信号传导的基因改变的小鼠。识别主机目标和 为患有衰弱甚至致命百日咳的人开发新的疗法 将对这种疾病产生重大的公共卫生影响。