Developmental Exposures to Arsenic: Pneumonia, Immunity, and Microbiomes (DEAPIM)

砷的发育暴露：肺炎、免疫和微生物组 (DEAPIM)

• 批准号: 10745882
• 负责人: SARAH J BLOSSOM
• 金额: $ 73.53万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-05 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745882
• 关键词: 16S ribosomal RNA sequencing; Accounting; Affect; Age; Air; Animal Model; Animals; Antibody Response; Antibody titer measurement; Arsenic; B-Cell Development; Bangladesh; Birth; Bone Marrow; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell surface; Cells; Cessation of life; Child; Childhood; Color; Communities; Complex; DNA Damage; DNA Repair; Data; Dendritic Cells; Development; Dose; Environmental Pollutants; Exposure to; Flow Cytometry; Food; Genes; Goals; Granzyme; Health; Hospitalization; Human; Immune; Immune system; Immunity; Immunologic Markers; Immunology procedure; Impairment; Incidence; Infection; Lead; Length; Life; Link; Lymphocyte; Measures; Mediating; Memory; Metagenomics; Morbidity - disease rate; Mothers; Nasopharynx; Outcome; Pathway interactions; Peripheral Blood Mononuclear Cell; Play; Pneumococcal vaccine; Pneumonia; Predisposition; Pregnancy; Production; Proliferating; Quantitative Reverse Transcriptase PCR; Regulatory T-Lymphocyte; Research; Resistance to infection; Respiratory Tract Infections; Risk; Role; Shotguns; Signal Transduction; Streptococcus pneumoniae; T cell differentiation; T-Cell Activation; T-Cell Development; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thymus Gland; Time; Toxic effect; Vaccination; Vaccines; adaptive immunity; bacteriome; booster vaccine; cohort; cytokine; drinking water; early life exposure; effector T cell; epidemiology study; exposed human population; genotoxicity; global health; gut microbiome; gut microbiota; immune function; immunoregulation; in utero; metagenomic sequencing; microbial; microbial community; microbiome; microbiota; monocyte; mortality; perforin; prenatal exposure; respiratory; response; stem cells; vaccine efficacy; vaccine response

ABSTRACT Exposure of human populations to arsenic via drinking water, air, and food is associated with significant morbidity and mortality. Along with impairments in immune function, an increased susceptibility to pneumonia has been observed in children exposed to high levels of arsenic. Pneumonia is a major global health concern accounting for 70% of pediatric hospitalizations in the US alone. Epidemiological studies indicate a decrease in the efficacy of respiratory vaccines in arsenic-exposed children. While vaccine efficacy is largely dependent on host immune function, recent evidence indicates that the gut microbiome may also play a role. However, the interrelationship of immune function and the microbiome on vaccine response in arsenic-exposed children has not been studied. It is likely that early exposures to arsenic compromise vaccines protecting against Streptococcus pneumoniae, the most common bacterial cause of pneumonia. The Scientific Premise is that Early life and in utero arsenic exposure in children leads to alterations in adaptive immunity via dysregulation of lymphocyte development and function. The impairment in these immune cells is responsible for decreases in protection from upper airway infections (such as S. pneumoniae) due to decreased vaccine PCV10 efficacy, as measured by S. pneumoniae nasopharyngeal (NP) carriage and anti-PCV circulating antibody titers. We also posit that arsenic disrupts the gut microbiome which may alter vaccine efficacy, due to altered adaptive T cell development. In Aim 1, we test the hypothesis that arsenic exposure in utero and during early life in children (1-2 year) leads to (a) impaired PCV10 antibody responses following a booster dose of PCV10, and (b) influences the NP microbiota diversity and the S. pneumoniae carriage. We will measure PCV10 titers and NP carriage using qRT-PCR and full length 16s rRNA sequencing. In Aim 2, we test the hypothesis that alterations in immune function and development are associated with early life arsenic exposure, leading to compromised host immunity. These measures include PBMC immune biomarkers and functional immune assays including: a) cell surface markers (CSM = T, B, NK, monocyte/dendritic cells, memory effector T cells) and the Th cell subsets (Th1, Th2, Th4, Th17, Treg) using 11-color flow cytometry; b) T cell proliferation; c) ex vivo cytokine production. In Aim 3 we test the hypothesis that differences in functional gut microbial composition are influenced by immune development and immune function. We will assess the gut bacterial microbiome by shotgun metagenomics and correlations with; a) PCV10 titers and the pneumococcal carriage (Aim1) and b) changes in immune markers/function (Aim 2). The study will be conducted among 400 children in Bangladesh ages between 1 and 2 years. Mothers of the participating children are part of a birth cohort and are followed throughout their pregnancy, and children are extremely well characterized for arsenic exposure in utero. These studies will provide new evidence on altered PCV vaccine response and the importance of the gut microbiome in adverse health outcomes associated with arsenic.

抽象的 通过饮用水，空气和食物接触人类人群与砷的暴露与大量有关 发病率和死亡率。随着免疫功能的损害，对肺炎的敏感性增加 在暴露于高水平砷的儿童中已经观察到。肺炎是全球主要的健康问题 仅在美国就占小儿住院的70％。流行病学研究表明下降 呼吸疫苗在暴露于砷的儿童中的功效。疫苗功效在很大程度上取决于 宿主免疫功能，最近的证据表明肠道微生物组也可能起作用。但是， 免疫功能的相互关系和暴露于砷的儿童疫苗反应的微生物组具有 没有被研究。早期暴露于砷妥协的疫苗防止疫苗 肺炎链球菌，这是肺炎最常见的细菌原因。科学前提是 儿童的早期和子宫砷暴露会导致通过失调的适应性免疫改变 淋巴细胞发育和功能。这些免疫细胞的损伤负责减少 由于疫苗PCV10疗效降低，防止上空气道感染（例如肺炎链球菌） 通过肺炎链球菌鼻咽（NP）运输和抗PCV循环抗体滴度测量。我们也是 假定砷会破坏肠道微生物组，该肠道微生物组可能会因自适应T细胞的改变而改变疫苗功效 发展。在AIM 1中，我们检验了子宫内砷暴露和儿童早期的假设 （1 - 2年）导致（a）加强剂量PCV10后的PCV10抗体反应受损，（b） 影响NP菌群多样性和肺炎链球菌。我们将测量PCV10滴度和NP 使用QRT-PCR和全长16S rRNA测序的运输。在AIM 2中，我们检验了改变的假设 在免疫功能和发育中，早期砷的暴露与之相关，导致受损 宿主免疫。这些措施包括PBMC免疫生物标志物和功能免疫测定法，包括： A）细胞表面标记（CSM = T，B，NK，单核细胞/树突状细胞，记忆效应T细胞）和TH细胞 使用11色流式细胞术，子集（Th1，Th2，Th4，Th17，Treg）； b）T细胞增殖； c）离体细胞因子 生产。在AIM 3中，我们测试了功能性肠道微生物组成差异的假设是 受免疫发育和免疫功能的影响。我们将通过 shot弹枪宏基因组学和与之相关； a）PCV10滴度和肺炎球菌运输（AIM1）和B） 免疫标记/功能的变化（AIM 2）。该研究将在孟加拉国的400名儿童中进行 年龄在1至2岁之间。参与儿童的母亲是分娩队列的一部分，遵循 在整个怀孕期间，儿童在子宫内的砷暴露均具有非常好的特征。这些 研究将提供有关PCV疫苗反应改变和肠道微生物组的重要性的新证据 与砷有关的不利健康结果。