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: 10408840
• 负责人: Karen Scanlon
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-21 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408840
• 关键词: Adopted; Adult; Age; Anti-Inflammatory Agents; Antigen-Presenting Cells; Bacteremia; Bordetella pertussis; C57BL/6 Mouse; Catabolism; Cause of Death; Cells; Cessation of life; Clinical Trials; Communicable Diseases; Data; Disease; Disease Outcome; Disease model; Drug Targeting; Enzymes; Epithelial Cells; FRAP1 gene; Fetus; Foundations; Future; Genes; Grant; Harvest; Health; Immune; Immune response; Immunity; Infant; Infection; Infectious Agent; Inflammation; Inflammatory; Kinetics; Knowledge; Kynurenine; Leukocytosis; Life Cycle Stages; Lung; Malignant Neoplasms; Maternal-Fetal Exchange; Metabolic; Modification; Mus; Natural Immunity; Nature; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pertussis; Pharmaceutical Preparations; Phenotype; Play; Predisposition; Production; Proteins; Pulmonary Hypertension; Research; Role; Severities; Stimulus; Structure of parenchyma of lung; Therapeutic; Tryptophan; Tryptophan 2,3 Dioxygenase; Tryptophan Metabolism Pathway; Up-Regulation; White Blood Cell Count procedure; Work; adaptive immunity; age related; aged; effective therapy; functional outcomes; immune function; immunopathology; improved; infancy; infant infection; infant outcome; inhibitor; lung colonization; macrophage; mortality risk; mouse model; neonatal human; novel therapeutics; pathogen; protein expression; response; transcriptome sequencing; transcriptomics

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.

项目摘要 对感染的免疫反应是动态的，在整个生命过程中发生了变化。早期致病性侮辱 年龄产生的免疫力与成年人的典型反应不同，婴儿采用 一种更加静止的防御策略，促炎性较少，耐受性较高。这种方法 通过限制免疫病理学和产生强大炎症的代谢需求，使婴儿受益， 但这也使婴儿更容易受到细菌败血症的影响和感染性疾病的严重结果。 吲哚胺2,3-二加氧酶（IDO）驱动kynurenine途径中的色氨酸分解代谢，以促进 耐受性免疫表型。该分子在播放的母亲界面上高度表达 在孕产妇容忍胎儿中的重要作用，但伊多在婴儿免疫中的作用尚未 决定。我们假设IDO是婴儿时期先天和适应性免疫的关键调节者 伊多（Ido）增强的行动增加了婴儿对感染的敏感性。 我们使用Bordetella budtussis（BP）小鼠模型来识别与年龄相关的感染反应。 bp- 诱发疾病的婴儿最严重，大多数感染引起的死亡发生在老年人中 <3个月。婴儿BP感染与细菌负荷增加和全身性相关 在感染成年人中未观察到的病理。在检查肺BP诱导基因的RNASEQ研究中 受宿主年龄差异调节的，我们发现婴儿小鼠的感染显着导致 与成人感染相比，IDO1上调更大。另外，BP感染增加了细胞内蛋白 IDO在肺抗原呈现细胞和从婴儿小鼠中收获但不是成年的上皮细胞中的表达 老鼠。这些结果支持以下假设：IDO响应与年龄有关，并增强了 感染引起的伊多（Ido）早年。此外，婴儿小鼠的IDO缺乏导致肺部降低 BP定殖并减少白细胞增多，BP诱导的关键婴儿特异性全身表现 疾病。因此，初步数据表明IDO功能可增强细菌感染和发病机理 在婴儿中。在此提案中，我们将扩展这些发现，以探索与年龄相关的BP调节的动力学 IDO诱导和活动以及婴儿IDO诱导的机制。我们还将确定影响 IDO对BP发病机理的其他年龄相关结果以及IDO对先天和自适应的影响 免疫细胞表型。这项工作产生的数据将有助于理解独特 国防策略从小就使用，并突出伊多（Ido）是婴儿免疫的关键调节者。伊多（Ido）靶向 药物正在接受临床试验作为癌症治疗。因此，如果IDO耗竭受益于婴儿的结果 感染，这些药物可能会迅速作为婴儿感染的治疗剂。