Development of Localized T Cell Immunity in Pediatric Respiratory Tract Infection

小儿呼吸道感染中局部 T 细胞免疫的发展

• 批准号: 10524045
• 负责人: Thomas Connors
• 金额: $ 19.46万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-05 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524045
• 关键词: Acute Lung Injury; Address; Affect; Age; Ambulatory Surgical Procedures; Blood; Cell surface; Cells; Child; Childhood; Clinic; Clinical; Consensus; Critical Care; Critical Illness; Data; Development; Diagnostic; Disease; Elderly; Environment; Environmental Exposure; Flow Cytometry; Foundations; Future; Gene Expression; Gene Expression Profiling; Generations; Genetic Transcription; Goals; Guidelines; Health; Hour; Human; Hyperactivity; Immune response; Immune system; Immunity; Immunologics; Infant; Infection; Investigation; K-Series Research Career Programs; Life; Lower respiratory tract structure; Lung; Lymphoid Tissue; Mechanical ventilation; Mediating; Memory; Mentors; Molecular Analysis; Mucous Membrane; Mus; Nature; Outpatients; Pathway interactions; Patient Recruitments; Patients; Pediatric Acute Respiratory Distress Syndrome; Physicians; Population; Process; Production; Program Development; Regimen; Regulation; Regulatory T-Lymphocyte; Research Personnel; Resources; Respiratory Failure; Respiratory System; Respiratory Tract Infections; Role; Sampling; Scientist; Severities; Severity of illness; T cell differentiation; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; T-bet protein; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Tonsillar Tissue; Training; Upper respiratory tract; Viral; Viral Respiratory Tract Infection; Virus Diseases; acute infection; adaptive immune response; career development; chemokine receptor; clinically relevant; cytokine; design; early childhood; effector T cell; experience; high dimensionality; human tissue; improved; infancy; insight; medical attention; mouse model; neonatal mice; pathogen; pediatric patients; prevent; preventive intervention; prognostic; prognostication; pulmonary function; receptor expression; response; targeted treatment; terminally differentiated effector memory (TEM) T cells; tissue resident memory T cell; transcription factor; transcriptome; transcriptome sequencing; translational study

7. PROJECT SUMMARY ABSTRACT Dr. Connors is a Pediatric Critical Care Physician Scientist investigating the generation and establishment of protective adaptive immune responses in infants and young children, particularly in the context of viral respiratory tract infections (VRTI). VRTI are ubiquitous in early life and commonly represent the first major challenge to the developing immune system. The majority of children clear infection without requiring medical attention, however severe disease from VRTI is the leading cause of respiratory failure necessitating mechanical ventilation during infancy. Importantly, associations between early life immune responses to infections and environmental exposures have been made to alterations in pulmonary function in later life. As immune responses in early life are formative for future protection from pathogens, aberrant responses in early life can have enduring repercussions. Differentiation of T cells to effector and memory subsets is required for viral clearance and establishment of protective immunity. Mouse models have demonstrated the importance of resident memory T cells (Trm) in mediating optimal protection. However neonatal mice T cells demonstrate transcriptionally distinct responses favoring the generation of terminally differentiated effector T cells over the establishment of Trm. Studies of human tissue have shown that T cells in tissue are predominately regulatory (Treg) in nature during infancy with few Trm. Importantly local T cell responses during VRTI are associated with disease severity in infants and children. The T cell subsets mediating protection during acute infection and the mechanisms leading to the establishment of long lived memory subsets remains uncharacterized in early life. Our central hypothesis is that protection from VRTI relies on the local adaptive immune response and aberrant immune responses during the formative window of infancy are associated with clinical severity. The aims of this proposal are 1) Determine pathways for T cell differentiation in early life and 2) Define the role of T cell subsets in VRTI induced Pediatric Acute Respiratory Distress Syndrome (PARDS). This career development award represents a crucial step in attaining the candidate’s long-term goal of transitioning to an independent researcher focused on translational studies of adaptive immune responses and critical illness in children. The academic, mentoring, training, and clinical opportunities afforded by the candidate’s current environment provide the perfect venues for successful completion of this project and for Dr. Connors to achieve his goal.

7.项目摘要 博士Connors是一名儿科重症监护医师科学家，负责调查 婴儿和幼儿的保护性适应性免疫反应，特别是在病毒感染的情况下， 呼吸道感染（VRTI）。VRTI在早期生活中普遍存在，通常代表第一个主要的 对免疫系统发育的挑战。大多数儿童在不需要医疗的情况下清除感染 注意，然而，VRTI引起的严重疾病是呼吸衰竭的主要原因， 婴儿期的机械通气。重要的是，早期生命免疫反应与 感染和环境暴露已经导致了以后生活中肺功能的改变。作为 早期生命中的免疫应答是形成未来对病原体的保护的，早期生命中的异常应答 生命会产生持久的影响。T细胞分化为效应子和记忆子亚群是免疫调节所必需的。 病毒清除和保护性免疫的建立。小鼠模型已经证明了 常驻记忆T细胞（Trm）介导最佳保护。然而，新生小鼠的T细胞显示， 转录上不同的反应有利于产生终末分化的效应T细胞超过 建立Trm。对人体组织的研究表明，组织中的T细胞主要是调节性的， （Treg）在婴儿期的性质，很少Trm。重要的是，VRTI期间的局部T细胞反应与 与婴儿和儿童的疾病严重程度有关。T细胞亚群介导急性感染时的保护作用 而导致长寿命记忆子集建立的机制仍然没有得到表征， 早年生活我们的中心假设是，VRTI的保护依赖于局部适应性免疫反应， 在婴儿期形成窗口期的异常免疫应答与临床严重性相关。 该提案的目的是：1）确定T细胞在生命早期分化的途径; 2）确定T细胞在生命早期分化中的作用。 VRTI诱导的小儿急性呼吸窘迫综合征（PARDS）T细胞亚群的变化。这个职业 发展奖代表了实现候选人过渡到一个长期目标的关键一步 独立研究人员专注于适应性免疫反应和危重病的转化研究， 孩子候选人目前的学术，指导，培训和临床机会 环境提供了完美的场地，成功完成这个项目，并为博士康纳斯， 实现他的目标。

项目成果

Ventricular Function and Tissue Characterization By Cardiac MRI in Children Following Hospitalization for Multisystem Inflammatory Syndrome in Children (MIS-C): A Prospective Study.

儿童多系统炎症综合征 (MIS-C) 住院后通过心脏 MRI 进行心室功能和组织表征：一项前瞻性研究。

• DOI: 10.21203/rs.3.rs-1254952/v1
• 发表时间: 2022
• 期刊: Research square
• 作者: Dilorenzo,MichaelP;Farooqi,KanwalM;Shah,AmeeM;Channing,Alexandra;Harrington,JamieK;Connors,ThomasJ;Martirosyan,Karen;Krishnan,UshaS;Ferris,Anne;Weller,RachelJ;Farber,DonnaL;Milner,JoshuaD;Gorelik,Mark;Rosenzweig,ErikaB
• 通讯作者: Rosenzweig,ErikaB

Ventricular function and tissue characterization by cardiac magnetic resonance imaging following hospitalization for multisystem inflammatory syndrome in children: a prospective study.

• DOI: 10.1007/s00247-022-05521-5
• 发表时间: 2023-03
• 期刊: PEDIATRIC RADIOLOGY
• 影响因子: 2.3
• 作者: DiLorenzo, Michael P.;Farooqi, Kanwal M.;Shah, Amee M.;Channing, Alexandra;Harrington, Jamie K.;Connors, Thomas J.;Martirosyan, Karen;Krishnan, Usha S.;Ferris, Anne;Weller, Rachel J.;Farber, Donna L.;Milner, Joshua D.;Gorelik, Mark;Rosenzweig, Erika B.;Anderson, Brett R.
• 通讯作者: Anderson, Brett R.

SARS-CoV-2 infection generates tissue-localized immunological memory in humans.

• DOI: 10.1126/sciimmunol.abl9105
• 发表时间: 2021-11-19
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Poon MML;Rybkina K;Kato Y;Kubota M;Matsumoto R;Bloom NI;Zhang Z;Hastie KM;Grifoni A;Weiskopf D;Wells SB;Ural BB;Lam N;Szabo PA;Dogra P;Lee YS;Gray JI;Bradley MC;Brusko MA;Brusko TM;Saphire EO;Connors TJ;Sette A;Crotty S;Farber DL
• 通讯作者: Farber DL

Impact and Clinical Implications of Prematurity on Adaptive Immune Development.

• DOI: 10.1007/s40124-020-00234-5
• 发表时间: 2020-12
• 期刊: Current pediatrics reports
• 影响因子: 1.9
• 作者: Idzikowski E;Connors TJ
• 通讯作者: Connors TJ

Distinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19 clinical spectrum.

• DOI: 10.1038/s41590-020-00826-9
• 发表时间: 2021-01
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Weisberg SP;Connors TJ;Zhu Y;Baldwin MR;Lin WH;Wontakal S;Szabo PA;Wells SB;Dogra P;Gray J;Idzikowski E;Stelitano D;Bovier FT;Davis-Porada J;Matsumoto R;Poon MML;Chait M;Mathieu C;Horvat B;Decimo D;Hudson KE;Zotti FD;Bitan ZC;La Carpia F;Ferrara SA;Mace E;Milner J;Moscona A;Hod E;Porotto M;Farber DL
• 通讯作者: Farber DL