CD8+ tissue-resident immunity to primary and heterotypic Influenza A controlled by commensal microbiota

CD8 对原发性和异型甲型流感的组织驻留免疫力由共生微生物群控制

• 批准号: 10708804
• 负责人: Joseph Jacob Stevens
• 金额: $ 2.71万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10708804
• 关键词: Adoptive Transfer; Adult; Affect; Antibiotic Therapy; Antibiotics; Automobile Driving; Behavior Control; Biological Assay; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cellular Assay; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cessation of life; Childhood; Chromatin; Clinic; Complex; Data; Development; Early identification; Epigenetic Process; Exposure to; Flow Cytometry; Foundations; Frequencies; Future; Gene Expression; Genetic Transcription; Host Defense; Immune; Immunity; Immunotherapeutic agent; Impairment; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A virus; Knowledge; Laboratories; Life; Lower Respiratory Tract Infection; Lung; Measurement; Measures; Mediating; Memory; Morbidity - disease rate; Mus; Neonatal; Neonatal Intensive Care Units; Outcome; Pediatric Hospitals; Physicians; Pneumonia; Population; Predisposition; Premature Infant; Production; Proliferating; Publishing; RNA; Reporting; Risk; Role; Scientist; Signal Transduction; Suspensions; T-Lymphocyte; Testing; Tissues; Transcription Alteration; Transposase; Vaccines; Viral Load result; Viral Pneumonia; Virus; Virus Diseases; Work; age group; career; cell behavior; commensal microbes; cross immunity; cytokine; cytotoxicity; design; doctoral student; gene regulatory network; influenzavirus; insight; interstitial; mortality; neonatal mice; neonatal pneumonia; neonate; new therapeutic target; novel; pathogen; postnatal; transcription factor; transcription regulatory network

Project Summary/Abstract Neonates have the highest infection-related mortality of any age group with viral pneumonia causing the majority of these estimated 1 million deaths per year. A majority of neonates in the neonatal intensive care unit (NICU) receive empiric antibiotic therapy. This antibiotic exposure dysregulates the development of immunity, including influenza-specific CD8+ T cells, although exactly how early-life antibiotic exposure affects the formation and function of tissue-resident CD8+ T cells is unclear. With their canonical role as adaptive responders to viral infection, CD8+ T cells are key effector immune cells in both immediate and long-term host defense against serious viral pneumonia. It is essential to better define how exactly early-life antibiotic exposure disrupts tissue-resident CD8+ T cell formation and function in order to lessen the substantial pneumonia-related mortality in neonates. Preliminary flow cytometry data in this proposal shows that early-life antibiotic exposure reduces the formation of influenza-specific CD8+ T cells, which leads to higher viral burden and morbidity. Preliminary single cell RNA (scRNA-) and single cell Assay for Transposase-accessible Chromatin sequencing (scATACseq) data shows a similar reduction in lung CD8+ T cells that is controlled by specific alterations in gene regulatory networks. This data drives the overall hypothesis of this proposal that early-life antibiotic exposure leads to a decrease in the formation and functions of tissue-resident CD8+ T cells following both primary and heterotypic Influenza A infection. This proposal will test this hypothesis by determining the effect of early-life antibiotic exposure on the formation and function of CD8+ T cells in the lungs following challenge with Influenza A (Aim 1) and determining regulatory mechanisms governing how this early-life antibiotic exposure affects the functions of CD8+ T cells (Aim 2). Collectively, this work will provide novel, mechanistic insights into how early-life antibiotic exposure is affecting the functions of influenza-specific tissue-resident CD8+ T cells. These Aims expect to show an antibiotic-mediated reduction in CD8+ T cell cytotoxicity, cytokine production, and proliferation, as well as changes in specific gene regulatory networks underlying the functional dysregulation. The candidate driving this proposal is currently an MD/PhD student at Cincinnati Children’s Hospital in the laboratory of Dr. Hitesh Deshmukh, who will use this proposal to set a foundation for an independent career as a physician-scientist. The candidate will use this proposal to support his future in the clinic as a pediatric intensivist, where findings from this proposal will uncover new strategies leading to better outcomes for the most vulnerable neonates.

项目摘要/摘要 新生儿的病毒性肺炎的任何年龄段与感染相关的死亡率最高 造成这些估计每年100万人死亡的大多数。大多数新生儿 新生儿重症监护病房（NICU）接受经验性抗生素疗法。这种抗生素暴露 免疫力的发育失调，包括影响特定的CD8+ T细胞，但是 确切的早期抗生素暴露如何影响组织居民的形成和功能 CD8+ T细胞尚不清楚。 CD8+作为对病毒感染的适应性反应者的规范作用 T细胞是立即和长期宿主防御的关键效应免疫球 严重的病毒性肺炎。更好地定义如何确切地定义早期生命的抗生素暴露是至关重要的 破坏组织居住的CD8+ T细胞形成和功能，以减少大量 新生儿中与肺炎相关的死亡率。此提案中的初步流式细胞仪数据显示 这种早期寿命的抗生素暴露减少了影响特异性CD8+ T细胞的形成， 导致更高的病毒灼伤和发病率。初步单细胞RNA（SCRNA-）和单细胞 转座酶可访问的染色质测序（SCATACSEQ）数据的测定数据显示了相似的 肺CD8+ T细胞的减少，该细胞受基因调节网络的特异性改变控制。 该数据推动了该提议的总体假设，即早期抗生素暴露 导致组织居住的CD8+ T细胞的形成和功能下降 原发性和异型型流感感染。该建议将通过 确定早期寿命抗生素暴露对CD8+ T形成和功能的影响 肺中的肺部细胞挑战流感A（AIM 1）并确定调节 该早期抗生素暴露如何影响CD8+ T细胞功能的机制 （目标2）。总的来说，这项工作将为早期抗生素如何提供新颖的机械见解 暴露正在影响影响Za特异性组织居住的CD8+ T细胞的功能。这些目标 期望显示CD8+ T细胞细胞毒性，细胞因子产生的抗生素介导的降低， 和增殖以及特定基因调节网络的变化 功能失调。驾驶此建议的候选人目前是一名MD/PhD学生 Hitesh Deshmukh博士实验室的辛辛那提儿童医院，他们将使用此建议 为身体科学家建立独立职业的基础。候选人将使用此 提议以儿科强化主义者为基础，支持他在诊所的未来，从中的发现 提案将揭示新的策略，从而为最脆弱的新生儿带来更好的结果。