IDO promotes severe manifestations of B. pertussis infection in infants

项目摘要 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 年龄产生的免疫力与成人的典型反应不同， 一种更安静的防御策略，更少的促炎性和更耐疾病。这种方法 通过限制免疫病理学和产生强烈炎症的代谢需求而有益于婴儿， 但它也使婴儿更容易感染细菌性脓毒症和严重的传染病后果。 吲哚胺2，3-双加氧酶（IDO）驱动犬尿氨酸途径中的色氨酸催化剂，以促进 致耐受性免疫表型这种分子在母胎界面高度表达， IDO在母体对胎儿的耐受性中起重要作用，但IDO在婴儿免疫中的作用尚未确定。 测定我们假设IDO在婴儿期作为先天性和适应性免疫的关键调节因子 IDO增强的作用增加了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，以确定年龄相关的感染反应。血压 感染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 在受感染的成年人中未观察到的病理。在一项RNASeq研究中， 受宿主年龄的差异调节，我们发现，在幼鼠中感染， 比成人感染更大的Ido1上调。此外，Bp感染增加细胞内蛋白质 IDO在从幼年小鼠而非成年小鼠收获的肺抗原呈递细胞和上皮细胞中的表达 小鼠这些结果支持IDO反应与年龄相关的假设， 感染诱导的早期IDO。此外，IDO缺乏导致幼鼠肺功能下降， Bp定植和白细胞增多减少，这是Bp诱导的婴儿特异性全身性表现， 疾病因此，初步数据表明IDO的功能是增强细菌的感染性和致病性 在婴儿身上。在这项建议中，我们将扩展这些发现，以探讨与年龄相关的动力学的血压调节， IDO的诱导和活性以及婴儿IDO诱导的机制。我们还将确定 IDO对Bp发病机制的其他年龄相关结果以及IDO对先天和适应性 免疫细胞表型这项工作产生的数据将有助于了解独特的 在早期使用的防御策略，并强调IDO作为婴儿免疫的关键调节剂。IDO靶向 药物作为癌症治疗剂正在进行临床试验;因此，如果IDO消耗有益于婴儿的结果， 感染，这些药物可以迅速实施作为治疗婴儿感染。

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.