IDO promotes severe manifestations of B. pertussis infection in infants

项目总结 对感染的免疫反应是动态的，在整个生命过程中不断变化。早期病原性侮辱 年龄产生的免疫力与成年人的典型反应不同，婴儿会采用 一种更静态的防御策略，不那么促炎，更能容忍疾病。这种方法 通过限制免疫病理和产生强烈炎症的代谢需求而使婴儿受益， 但它也使婴儿更容易患上细菌性败血症和严重的传染病后果。 吲哚胺2，3-双加氧酶(IDO)在犬尿氨酸途径中驱动色氨酸分解代谢，促进 耐受性免疫表型。这种分子在母胎界面上高度表达，在那里发挥作用。 在母体对胎儿的耐受性中起着重要作用，但IDO在婴儿免疫中的作用尚未得到证实 下定决心。我们假设IDO在婴儿时期是先天免疫和获得性免疫的关键调节器。 而且，IDO增强了婴儿对感染的易感性。 我们使用百日咳波氏杆菌(BP)小鼠模型来识别与年龄相关的感染反应。BP- 诱发疾病在婴儿中最为严重，感染导致的死亡大多发生在老年人中。 &lt；3个月。婴儿BP感染与细菌负荷增加和系统性疾病的表现有关 在受感染的成年人身上没有观察到的病理。在一项检测肺BP诱导基因的RNAseq研究中 根据宿主年龄的不同，我们发现感染幼鼠会导致显著的 比成人感染更大的Ido1上调。此外，BP感染增加了细胞内蛋白质 IDO在幼鼠肺抗原提呈细胞和肺上皮细胞中的表达 老鼠。这些结果支持这样的假设，即IDO反应是与年龄相关的，具有增强的 感染引起的早年IDO。此外，乳鼠缺乏IDO可导致肺功能减退。 BP的定植和白细胞减少--BP诱发的关键的婴儿特异性全身表现 疾病。因此，初步数据表明，IDO具有增强细菌感染性和致病性的作用。 在婴儿身上。在这项提案中，我们将在这些发现的基础上，探索与年龄相关的血压调节动力学 IDO在婴幼儿体内的诱导和活性及其机制。我们还将确定影响 IDO对BP发病其他年龄相关结局的影响以及IDO对先天适应性的影响 免疫细胞表型。这项工作产生的数据将有助于理解独特的 早期使用的防御策略，并强调IDO是婴儿免疫的关键调节器。IDO-目标 作为癌症治疗药物的药物正在进行临床试验；因此，如果IDO耗尽有利于婴儿的结局 对于婴儿感染，这些药物可能会作为治疗药物迅速实施。

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.