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

基本信息

  • 批准号:
    10286308
  • 负责人:
  • 金额:
    $ 23.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-05-21 至 2023-04-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Immune responses to infection are dynamic, changing throughout the course of life. Pathogenic insult at early age generates immunity that is distinct from the typical responses characterized in adults, with infants adopting a more quiescent defense strategy that is less pro-inflammatory and more disease tolerant. This approach benefits the infant by limiting immunopathology and the metabolic demands of generating robust inflammation, but it also renders infants more susceptible to bacterial sepsis and severe outcomes of infectious disease. Indoleamine 2,3-dioxygenase (IDO) drives tryptophan catabolism in the kynurenine pathway to promote a tolerogenic immune phenotype. This molecule is highly expressed at the maternal-fetal interface where it plays an important role in maternal tolerance to the fetus but a role for IDO in infant immunity has yet to be determined. We hypothesize that IDO acts as a critical regulator of innate and adaptive immunity at infancy and that actions potentiated by IDO increase infant susceptibility to infection. We use a Bordetella pertussis (Bp) mouse model to identify age-related responses to infection. Bp- induced disease is most severe in infants, with the majority of infection-induced deaths occurring in those aged <3 months. Infant Bp infection is associated with increased bacterial loads and the manifestation of systemic pathologies that are not observed in infected adults. In an RNASeq study examining lung Bp-induced genes that were differentially regulated by host age, we found that infection in infant mice resulted in significantly greater Ido1 upregulation than adult infection. In addition, Bp infection increased intracellular protein expression of IDO in lung antigen presenting cells and epithelial cells harvested from infant mice but not adult mice. These results support the hypothesis that IDO responses are age-related, with enhanced production of infection-induced IDO at early age. Furthermore, IDO deficiency in infant mice resulted in decreased lung colonization by Bp and reduced leukocytosis, a critical infant-specific systemic manifestation of Bp-induced disease. Hence, preliminary data indicates that IDO functions to enhance bacterial infectivity and pathogenesis in infants. In this proposal, we will extend on these findings to explore the age-related kinetics of Bp-regulated IDO induction and activity and the mechanism of IDO induction in the infant. We will also determine the impact of IDO on other age-related outcomes of Bp pathogenesis and the effect of IDO on innate and adaptive immune cell phenotypes. Data generated by this work will contribute to the understanding of the unique defense strategies utilized at early age and highlight IDO as a critical regulator of infant immunity. IDO-targeted drugs are undergoing clinical trials as cancer therapeutics; hence, if IDO depletion benefits outcomes of infant infection, these drugs may be rapidly implemented as therapeutics for infant infection.
项目总结

项目成果

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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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    10241992
  • 财政年份:
    2018
  • 资助金额:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 项目类别:

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