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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结