IDO promotes severe manifestations of B. pertussis infection in infants
IDO promotes severe manifestations of B. pertussis infection in infants
批准号:
10408840
负责人:
Karen Scanlon
金额:
$19.31万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-05-21 至 2025-04-30
关键词:
AdoptedAdultAgeAnti-Inflammatory AgentsAntigen-Presenting CellsBacteremiaBordetella pertussisC57BL/6 MouseCatabolismCause of DeathCellsCessation of lifeClinical TrialsCommunicable DiseasesDataDiseaseDisease OutcomeDisease modelDrug TargetingEnzymesEpithelial CellsFRAP1 geneFetusFoundationsFutureGenesGrantHarvestHealthImmuneImmune responseImmunityInfantInfectionInfectious AgentInflammationInflammatoryKineticsKnowledgeKynurenineLeukocytosisLife Cycle StagesLungMalignant NeoplasmsMaternal-Fetal ExchangeMetabolicModificationMusNatural ImmunityNatureOutcomePathogenesisPathogenicityPathologyPathway interactionsPertussisPharmaceutical PreparationsPhenotypePlayPredispositionProductionProteinsPulmonary HypertensionResearchRoleSeveritiesStimulusStructure of parenchyma of lungTherapeuticTryptophanTryptophan 2,3 DioxygenaseTryptophan Metabolism PathwayUp-RegulationWhite Blood Cell Count procedureWorkadaptive immunityage relatedagedeffective therapyfunctional outcomesimmune functionimmunopathologyimprovedinfancyinfant infectioninfant outcomeinhibitorlung colonizationmacrophagemortality riskmouse modelneonatal humannovel therapeuticspathogenprotein expressionresponsetranscriptome sequencingtranscriptomics
中文摘要
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。
英文摘要
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.
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会议论文
Age-related skewing of angiotensin II signaling potentiates B. pertussis-induced pulmonary hypertension
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批准号:10087891
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项目类别:
-
资助金额:$19.31万
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财政年份:2020
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负责人:Karen Scanlon
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依托单位:
海外基金