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.

项目总结