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
• 负责人: NICHOLAS H CARBONETTI
• 金额: $ 23.18万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286308
• 关键词: Adopted; Adult; Age; Anti-Inflammatory Agents; Antigen-Presenting Cells; 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; Sepsis; 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/antagonist; 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.

项目概要 对感染的免疫反应是动态的，在整个生命过程中不断变化。早期致病性损伤 年龄产生的免疫力不同于成人的典型反应，婴儿采用 一种更静态的防御策略，促炎性较低，疾病耐受性更强。这种做法 通过限制免疫病理学和产生强烈炎症的代谢需求，对婴儿有益​​， 但它也使婴儿更容易患细菌性败血症和传染病的严重后果。 吲哚胺 2,3-双加氧酶 (IDO) 驱动犬尿氨酸途径中的色氨酸分解代谢，从而促进 耐受性免疫表型。该分子在其发挥作用的母胎界面高度表达 IDO 在母亲对胎儿的耐受性中发挥重要作用，但 IDO 在婴儿免疫中的作用尚未确定 决定。我们假设 IDO 作为婴儿期先天性和适应性免疫的关键调节剂 IDO 增强的作用会增加婴儿对感染的易感性。 我们使用百日咳博德特氏菌 (Bp) 小鼠模型来识别与年龄相关的感染反应。 BP- 引起的疾病在婴儿中最为严重，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感染表现相关 在感染的成人中未观察到的病理。在一项检查肺 Bp 诱导基因的 RNASeq 研究中 受宿主年龄的差异调节，我们发现幼年小鼠的感染导致显着 Ido1 的上调程度高于成人感染。此外，Bp感染增加细胞内蛋白质 IDO 在从婴儿小鼠而非成年小鼠收集的肺抗原呈递细胞和上皮细胞中表达 老鼠。这些结果支持这样的假设：IDO 反应与年龄相关，随着 IDO 产生的增加 早年感染引起的 IDO。此外，幼年小鼠 IDO 缺乏导致肺功能下降 Bp 定植和白细胞增多症减少，这是 Bp 诱导的婴儿特有的关键全身表现 疾病。因此，初步数据表明 IDO 具有增强细菌感染性和发病机制的作用 在婴儿中。在本提案中，我们将扩展这些发现，探索 Bp 调节的年龄相关动力学 婴儿 IDO 诱导和活性以及 IDO 诱导机制。我们还将确定影响 IDO 对 Bp 发病机制其他年龄相关结果的影响以及 IDO 对先天性和适应性的影响 免疫细胞表型。这项工作生成的数据将有助于理解独特的 早期使用的防御策略，强调 IDO 作为婴儿免疫力的关键调节剂。以 IDO 为目标 药物正在作为癌症治疗药物进行临床试验；因此，如果 IDO 消耗有益于婴儿的结局 感染，这些药物可能会迅速用作婴儿感染的治疗方法。