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:
  • 金额:
    $ 38.63万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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NICHOLAS H CARBONETTI其他文献

NICHOLAS H CARBONETTI的其他文献

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{{ truncateString('NICHOLAS H CARBONETTI', 18)}}的其他基金

Systems-Level Research in Microbial Pathogenesis
微生物发病机制的系统级研究
  • 批准号:
    10671611
  • 财政年份:
    2022
  • 资助金额:
    $ 38.63万
  • 项目类别:
Age-dependent role of interferon lambda in protection against pertussis lethality in infants
干扰素 lambda 在防止婴儿百日咳致死方面的年龄依赖性作用
  • 批准号:
    10591086
  • 财政年份:
    2022
  • 资助金额:
    $ 38.63万
  • 项目类别:
IDO promotes severe manifestations of B. pertussis infection in infants
IDO 促进婴儿百日咳博德特氏菌感染的严重表现
  • 批准号:
    10286308
  • 财政年份:
    2021
  • 资助金额:
    $ 38.63万
  • 项目类别:
NK cell and interferon gamma deficiency in infant susceptibility to pertussis
NK细胞和γ干扰素缺乏导致婴儿对百日咳的易感性
  • 批准号:
    10369616
  • 财政年份:
    2021
  • 资助金额:
    $ 38.63万
  • 项目类别:
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:
    10078317
  • 财政年份:
    2018
  • 资助金额:
    $ 38.63万
  • 项目类别:
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:
    10475402
  • 财政年份:
    2018
  • 资助金额:
    $ 38.63万
  • 项目类别:
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
  • 财政年份:
    2018
  • 资助金额:
    $ 38.63万
  • 项目类别:
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:
    10685140
  • 财政年份:
    2018
  • 资助金额:
    $ 38.63万
  • 项目类别:
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:
    10462744
  • 财政年份:
    2018
  • 资助金额:
    $ 38.63万
  • 项目类别:
Host-targeted therapeutics for pertussis in infants
婴儿百日咳的宿主靶向治疗
  • 批准号:
    9035033
  • 财政年份:
    2016
  • 资助金额:
    $ 38.63万
  • 项目类别:

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