Exploring human milk oligosaccharides and malaria risk in breastfed infants

探索母乳低聚糖和母乳喂养婴儿的疟疾风险

• 批准号: 10057627
• 负责人: Lars Bode
• 金额: $ 20.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057627
• 关键词: African; Anti-Inflammatory Agents; Antibodies; Antiinflammatory Effect; Antimalarials; Area; Biological Assay; Birth; Blood; Blood Circulation; Blood specimen; Breast Feeding; Breastfed infant; Cell Line; Cells; Childhood; Clinic Visits; Clinical Trials; Communicable Diseases; Conflict (Psychology); Country; Data; Development; Diagnosis; Dietary Intervention; Disease; Enzyme-Linked Immunosorbent Assay; Equation; Equilibrium; Erythrocytes; Falciparum Malaria; Goals; Growth; Health; High Pressure Liquid Chromatography; Human; Human Cell Line; Human Milk; Immune; Immunity; Immunology; Infant; Inflammation; Inflammatory; Ingestion; Intervention; Knowledge; Lead; Link; Macrophage Activation; Malaria; Maternal Age; Measurement; Measures; Mediating; Mediator of activation protein; Metadata; Methods; Modeling; Mothers; Natural Immunity; Nigerian; Oligosaccharides; Outcome; Parasites; Pathology; Phagocytosis; Plasma; Plasmodium falciparum; Play; Prevalence; Production; Reporting; Research; Rest; Risk; Risk Factors; Role; Sampling; Seasons; Statistical Models; Surface; Testing; Uganda; base; chemokine; cohort; cytokine; design; experience; insight; macrophage; malaria infection; migration; monocyte; mortality; neonate; novel; parity; prospective; receptor; recruit; response; sex; study population

ABSTRACT There is a significant burden of malaria in young African infants - the majority of whom are breastfed from birth up to 24 months. These `break through' malaria infections probably indicate incomplete protection by breastfeeding. There is a significant gap in our knowledge about antimalarial immunity mediated by breastfeeding and the factors involved. Our recent preliminary data demonstrated that high concentrations of specific human milk oligosaccharides (HMOs) in Ugandan mothers' milk are differentially associated with malaria risk in their infants. HMOs represent the third most abundant component in breast milk which, upon ingestion by infants, reach the systemic circulation where they directly engage innate immune cells through specific surface receptors. Studies involving ex vivo stimulation of human cells and cell lines demonstrated that HMOs modulate the functions of macrophages and monocytes in several ways. This includes inducing anti-inflammatory or proinflammatory responses, inducing or inhibiting monocyte or macrophage activation, inhibition of proliferation or migration, and enhancing phagocytosis. A human clinical trial involving infants fed 2'- fucosyllactose (2'FL) in formula confirmed the anti-inflammatory effect of 2'FL. HMO-mediated modulation of monocyte function is highly relevant to pediatric malaria which involves monocyte dysregulation and systemic inflammation. Our long-term goal is to elucidate the role of HMOs in early innate immunity against malaria. The objective of this project is to determine the relationship between HMOs in breast milk and infant blood, monocyte function, and malaria outcomes in breast-fed infants. The central hypothesis is that direct HMO modulation of monocytes tips the balance towards disease or protection during pediatric malaria and that differences in levels of specific HMOs are linked to different malaria outcomes. This hypothesis will be tested in two Specific Aims. Aim 1: To recruit a birth cohort and prospectively collect health metadata including malaria outcomes and concentrations of soluble monocyte activation markers, cytokines and chemokines in infants. A birth cohort of 388 mother-infant pairs will be recruited and infants followed over 18 months with blood sampling every month and during infant illness for malaria diagnosis, multiplex bead-based cytokine and chemokine assays and ELISA for soluble monocyte activation markers. Aim 2: To measure concentrations of HMOs in mothers' milk and infant plasma to assess their association with monocyte mediators and malaria outcomes in infants. We will measure concentrations of HMOs in mothers' milk and infant plasma monthly and during pediatric malaria attacks to identify HMOs that are associated with specific monocyte inflammatory cytokines and chemokines and activation markers which are, in turn, linked to distinct malaria outcomes. To account for correlation between multiple measurements in the same infant, the relationships between malaria outcomes, specific HMOs, and markers of monocyte function will be assessed by Generalized Estimating Equation method while controlling for covariates such as maternal age and parity, infant sex, season of sampling and other malaria risk factors. The team brings experience in malaria and HMO research plus access to a study population in Uganda. Together, these proposed exploratory studies will provide preliminary insights on the crucial role that HMOs play in malaria innate immunity. This project will set the stage for more powered mechanistic studies of HMO-monocyte interactions which will inform the design of novel antimalarial interventions. The results are generalizable to other regions with a high burden of malaria in young infants. The potential to move the field forward and make a sustainable impact is high.

抽象的 年轻的非洲婴儿有很大的疟疾负担 - 大多数人从出生到24岁都有母乳喂养 月份。这些“突破”疟疾感染可能表明通过母乳喂养不完全保护。有一个 我们对母乳喂养介导的抗疟疾免疫力和所涉及因素的差异。我们的 最近的初步数据表明，高浓度的特定人乳寡糖（HMO） 乌干达母亲的牛奶与婴儿的疟疾风险不同。 HMO代表第三个 母乳中的大量成分，婴儿摄入后，直接到达全身循环 通过特定的表面受体吸引先天免疫细胞。涉及人类细胞的体内刺激的研究和 细胞系表明HMOS通过多种方式调节巨噬细胞和单核细胞的功能。这包括 诱导抗炎或促炎反应，诱导或抑制单核细胞或巨噬细胞激活， 抑制增殖或迁移，并增强吞噬作用。涉及2'-婴儿的人类临床试验 配方中的岩藻酸酯（2'fl）证实了2'fl的抗炎作用。 HMO介导的调制 单核细胞功能与涉及单核细胞失调和全身性的小儿疟疾高度相关 炎。我们的长期目标是阐明HMO在早期对疟疾的先天免疫中的作用。 该项目的目的是确定母乳和婴儿血液中HMO之间的关系 母乳喂养婴儿的功能和疟疾结局。中心假设是单核细胞的直接HMO调节 提示在小儿疟疾期间疾病或保护的平衡以及特定HMO的水平的差异是 与不同的疟疾结局有关。该假设将以两个具体的目的进行检验。目标1：招募分娩队列 并前瞻性收集健康元数据，包括疟疾结果和可溶性单核细胞激活的浓度 婴儿的标记，细胞因子和趋化因子。将招募388对母亲的出生队列和婴儿 随后每月进行18个月的血液采样，在婴儿疾病期间进行疟疾诊断，多重诊断 可溶性单核细胞激活标记物的基于珠的细胞因子和趋化因子测定和ELISA。目标2：测量 母亲牛奶和婴儿血浆中HMO的浓度，以评估其与单核细胞介质的关联和 婴儿的疟疾结果。我们将每月测量母亲牛奶和婴儿血浆中HMO的浓度 在小儿疟疾攻击期间，以识别与特定单核细胞炎性细胞因子和 趋化因子和激活标志物反过来又与不同的疟疾结局有关。考虑相关性 在同一婴儿中的多个测量中，疟疾结果，特定HMO和 单核细胞功能的标记将通过一般估计方程方法进行评估，同时控制 孕产妇年龄和奇偶校验，婴儿性别，采样季节和其他疟疾危险因素等协变量。团队带来 疟疾和HMO研究的经验以及乌干达研究人群的机会。 这些拟议的探索性研究将共同​​提供有关HMO在疟疾中至关重要的作用的初步见解 先天免疫。该项目将为HMO单细胞相互作用的更多动力机械研究奠定阶段 将告知新型抗性干预措施的设计。结果可以推广到负担很高的其他地区 年轻婴儿的疟疾。向前推进该领域并产生可持续影响的潜力很高。