The Effect of Maternal Cells on Infant Immunity

母体细胞对婴儿免疫力的影响

• 批准号: 10319598
• 负责人: Whitney Elizabeth Harrington
• 金额: $ 17.07万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-12 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319598
• 关键词: Active Biological Transport; Adhesions; Affect; African; Allogenic; Antibiotics; Antigens; Automobile Driving; B-Lymphocytes; Bilateral; Birth; Cause of Death; Cell physiology; Cells; Child; Childhood; Clinical; Coculture Techniques; Communicable Diseases; DNA; Data; Diarrhea; Disease; Down-Regulation; Enrollment; Event; Exposure to; Fetal Development; Fetus; Fever; Flow Cytometry; Future; Health Campaign; Hospitalization; Human; Immune; Immune response; Immune system; Immunity; Immunization; Infant; Infant Development; Infection; Inflammation; Inflammatory; Inflammatory Response; Integrins; Intrinsic factor; Knowledge; Lead; Lower Respiratory Tract Infection; Maintenance; Malaria; Mali; Measures; Mediating; Microchimerism; Modeling; Morbidity - disease rate; Mothers; Parasitemia; Pathology; Perinatal; Phenotype; Placenta; Pneumonia; Predictive Factor; Predisposition; Pregnancy; Process; Public Health; Rattus; Recording of previous events; Regulation; Reproduction; Research; Risk; Role; Sampling; Second Pregnancy Trimester; Secondary to; Shapes; Signal Transduction; Suggestion; Syncytiotrophoblast; T-Lymphocyte; Testing; Umbilical Cord Blood; Vaccination; Vaccine Antigen; Vascular Endothelial Growth Factors; Water; Work; accurate diagnostics; base; cohort; cytokine; diarrheal disease; enzyme linked immunospot assay; exosome; experience; fetal; fetus cell; global health; infancy; infant infection; intergenerational; mortality; neonatal sepsis; neonate; novel strategies; offspring; pathogen; peripheral blood; placental malaria; postnatal; prevent; public health relevance; response; trafficking; transcriptome; transcriptome sequencing; vaccine access

Modified Project Summary/Abstract Section Despite large improvements in global childhood mortality in the last 20 years, an astonishing 5.9 million children died before their fifth birthday in 2015. Three of the top five causes of death are infectious, including pneumonia, diarrhea, and neonatal sepsis. Although extrinsic factors such as vaccination, access to clean water, antibiotics, and accurate diagnostics are targets of current public health campaigns, little is known about the host intrinsic factors that affect susceptibility to these illnesses. In particular, thus far overlooked is the role of a small number of maternal cells and DNA acquired by the fetus during pregnancy, known as maternal microchimerism, in infant infection. This proposal specifically seeks to understand the role of these maternal cells in shaping fetal and infant immune responses and subsequent protection from infectious diseases during childhood. We recently found that children with maternal microchimerism at delivery were more likely to become infected with malaria but, when infected, were less likely to become sick or to be hospitalized as compared to children without maternal microchimerism. This finding may imply a mechanism of natural “vaccination” whereby children experience infection but are protected from disease. We hypothesize that this effect is the result of maternal regulation of pro-inflammatory fetal and infant immune responses, limiting immune-mediated pathology, and that such regulation may extend to immune responses directed against other infections of global health importance. Using samples and data from offspring of US pregnancies as well as malaria-exposed pregnancies from Mali, we propose to identify the factors that determine the acquisition of maternal microchimerism, the ability of maternal cells to modulate the immune phenotype of the fetus and infant, and the role of maternal cells in protection from common childhood infections, including pneumonia and diarrhea. We anticipate that this study will demonstrate that acquired maternal cells influence fetal and infant immune responses, which would have broad implications for perinatal and postnatal infections and response to immunization. In addition, demonstrating that maternal cells provide protection against childhood infections would suggest an evolutionary benefit to maintaining this graft, emphasizing the importance of intergenerational immune interactions. Finally, identification of the factors that predict maternal microchimerism may lead to future targets for intentional modulation of maternal cells as a novel approach to prevent the immune-mediated morbidity and mortality associated with childhood infections of global health importance.

修改后的项目摘要/摘要部分 尽管全球儿童死亡率在过去20年里有了很大改善，但令人震惊的是，2015年有590万儿童在5岁生日之前死亡。前五大死因中有三个是传染性的，包括肺炎、腹泻和新生儿败血症。尽管接种疫苗、获得清洁水、抗生素和准确诊断等外在因素是当前公共卫生活动的目标，但对影响这些疾病易感性的宿主内在因素知之甚少。特别是，迄今为止被忽视的是胎儿在怀孕期间获得的少量母体细胞和DNA在婴儿感染中的作用，即母体微嵌合体。这项建议特别寻求了解这些母体细胞在形成胎儿和婴儿免疫反应以及随后保护儿童免受传染病侵袭方面的作用。我们最近发现，分娩时母亲微嵌合体的儿童更有可能感染疟疾，但与没有母亲微嵌合体的儿童相比，感染后患病或住院的可能性较小。这一发现可能暗示了一种自然的“疫苗接种”机制，即儿童受到感染，但受到保护，免受疾病侵袭。我们假设，这种效应是母体调节促炎症的胎儿和婴儿免疫反应的结果，限制了免疫介导的病理，并且这种调节可能延伸到针对其他全球卫生重要性感染的免疫反应。利用美国孕妇和马里疟疾孕妇后代的样本和数据，我们建议确定决定母体微嵌合体获得的因素、母体细胞调节胎儿和婴儿免疫表型的能力，以及母体细胞在预防常见儿童感染(包括肺炎和腹泻)中的作用。我们预计，这项研究将证明获得性母体细胞影响胎儿和婴儿的免疫反应，这将对围产期和出生后感染以及免疫反应产生广泛的影响。此外，证明母体细胞提供对儿童感染的保护将表明维持这种移植物在进化上的好处，强调代际免疫互动的重要性。最后，确定预测母体微嵌合体的因素可能导致未来有意调节母体细胞的目标，作为预防与全球卫生重要性的儿童感染相关的免疫介导的发病率和死亡率的新方法。

项目成果

In silico detection of SARS-CoV-2 specific B-cell epitopes and validation in ELISA for serological diagnosis of COVID-19.

• DOI: 10.1038/s41598-021-83730-y
• 发表时间: 2021-02-22
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Phan IQ;Subramanian S;Kim D;Murphy M;Pettie D;Carter L;Anishchenko I;Barrett LK;Craig J;Tillery L;Shek R;Harrington WE;Koelle DM;Wald A;Veesler D;King N;Boonyaratanakornkit J;Isoherranen N;Greninger AL;Jerome KR;Chu H;Staker B;Stewart L;Myler PJ;Van Voorhis WC
• 通讯作者: Van Voorhis WC

A Noninvasive Method to Sample Immune Cells in the Lower Female Genital Tract Using Menstrual Discs.

使用月经盘对女性下生殖道免疫细胞进行无创取样的方法。

• DOI: 10.4049/immunohorizons.2300105
• 发表时间: 2024
• 期刊: ImmunoHorizons
• 作者: Peters,MQuinn;Domenjo-Vila,Eva;Carlson,Marc;Armistead,Blair;Edlefsen,PaulT;Gasper,Melanie;Dabee,Smritee;Whidbey,Christopher;Jaspan,HeatherB;Prlic,Martin;Harrington,WhitneyE
• 通讯作者: Harrington,WhitneyE

Low rate of SARS-CoV-2 incident infection identified by weekly screening PCR in a prospective year-long cohort study.

• DOI: 10.1371/journal.pone.0274078
• 发表时间: 2022
• 期刊: PloS one
• 影响因子: 3.7

Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells.

• DOI: 10.3389/fphar.2021.765951
• 发表时间: 2021
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Okoloko O;Vanderwall ER;Rich LM;White MP;Reeves SR;Harrington WE;Barrow KA;Debley JS
• 通讯作者: Debley JS

Rapid decline of neutralizing antibodies is associated with decay of IgM in adults recovered from mild COVID-19.

• DOI: 10.1016/j.xcrm.2021.100253
• 发表时间: 2021-04-20
• 期刊: Cell reports. Medicine
• 作者: Harrington WE;Trakhimets O;Andrade DV;Dambrauskas N;Raappana A;Jiang Y;Houck J;Selman W;Yang A;Vigdorovich V;Yeung W;Haglund M;Wallner J;Oldroyd A;Hardy S;Stewart SWA;Gervassi A;Van Voorhis W;Frenkel L;Sather DN
• 通讯作者: Sather DN