Infant Mycotoxin Exposure and Mucosal Immune Activation in HIV-Endemic South Afri

艾滋病毒流行的南非婴儿霉菌毒素暴露和粘膜免疫激活

• 批准号: 9005861
• 负责人: Lianna F Wood
• 金额: $ 3.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2017-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005861
• 关键词: Adult; Africa South of the Sahara; Age; Blood; Blood Circulation; Breast Feeding; Cells; Cereals; Cessation of life; Child; Childhood; Clinic; Clinical; Clinical Research; Cluster Analysis; Communities; Complex; Computer Analysis; Country; Developed Countries; Developing Countries; Doctor of Philosophy; Environment; Environmental Risk Factor; Evaluation; Exposure to; Fellowship; Flow Cytometry; Food; Food Contamination; Fumonisin B1; Goals; HIV; HIV Infections; Health; Health Policy; Human Milk; Immune; Immune response; Immune system; In Vitro; Individual; Infant; Infant Health; Infant Mortality; Infection; Infiltration; Laboratories; Lead; Life; Mentorship; Migration Assay; Modeling; Mother-to-child HIV transmission; Mothers; Mucositis; Mucous Membrane; Multivariate Analysis; Mycotoxins; Oral cavity; Oral mucous membrane structure; Peripheral; Plasma; Play; Population; Predisposition; Production; Proteins; Proteomics; Public Health; Recruitment Activity; Regulation; Research; Resources; Role; Route; SIV; Sampling; Site; South Africa; South African; Systems Biology; Tissues; Transcript; Translational Research; Virus Replication; Work; base; chemokine; chemokine receptor; cytokine; cytotoxic; deoxynivalenol; experience; feeding; fungus; immune activation; immunoregulation; improved; in vivo; infant morbidity/mortality; insight; mortality; peripheral blood; pregnant; response; small molecule; transcriptomics; transmission process

DESCRIPTION (provided by applicant): At least 2 million South Africans live in informal settlements where nearly 20% of children die before the age of five. Infants in underdeveloped communities have elevated basal immune activation than their counterparts in developed countries, suggesting environmental factors may be responsible for this high mortality rate. Children in developing countries are frequently exposed to fungal, cytotoxic molecules, called mycotoxins, that can increase the pathogenisis of infections. In our study in Khayelitsha, South Africa, an informal settlement outside of Cape Town, we found a robust correlation between plasma Ochratoxin levels and proinflammatory cytokine and chemokine levels. Interestingly, mixed feeding, where breast milk is supplemented with other, potentially mycotoxin-contaminated foods, increases an infant's susceptibility to HIV by as much as 11 fold. I will use this known difference in HIV susceptibility to focus my study of mycotoxin-induced immune changes. Preliminary findings from our study of infant feeding practices in Khayelitsha shows a significantly larger CD4+ immune cell population in the oral mucosa of mixed fed infants, suggesting that mucosal inflammation may play a key role in increasing an infant's susceptibility to HIV. This study will investigate the role of mycotoxins in oral mucosa immune modulation, using ex vivo stimulations and samples from our infant feeding study in Khayelitsha. I hypothesize that mycotoxin exposure induces chemokine production in infant oral mucosa that preferentially recruits HIV target cells, increasing the susceptibility of the oral mucosa to HIV. y evaluation of mycotoxin exposure will focus on OTA, Deoxynivalenol (DON) and Fumonisin B1, the three mycotoxins that have been repeatedly shown to modulate immune responses in vitro and in vivo. Ex vivo stimulation of healthy, mycotoxin-unexposed, adult and infant blood and oral mucosa will be used to define the network of chemokines and chemokine receptors expressed by oral mucosa cells in response to stimulation with mycotoxins. Blood and oral mucosa samples from mixed fed infants in Khayelitsha will be used to elucidate the role of mycotoxin exposure on the immune state of South African infants. These studies will use a combination of transcriptomics, proteomics, flow cytometry and cell migration assays, which will be integrated into systems biology-based computational analyses and multivariate analyses to model the complex interaction between chemokines, cell recruitment and innate immune factors. The work outlined above will significantly improve our understanding of the impact of food contaminants on infant mortality in developing countries. Understanding the role of mycotoxins in modulating infant immune systems and identifying contaminants with the greatest impact on infant health will permit countries with limited resources to prioritize regulation of these specific contaminant and may lead to the identification of other environmental immune-modulating agents that impact infant morbidity and mortality in the developing world.

描述（由申请人提供）：至少有 200 万南非人生活在非正规住区，其中近 20% 的儿童在五岁之前死亡。欠发达社区的婴儿的基础免疫激活水平高于发达国家的婴儿，这表明环境因素可能是导致高死亡率的原因。发展中国家的儿童经常接触真菌、细胞毒性分子，称为霉菌毒素，会增加感染的发病机制。在南非卡耶利沙（开普敦郊外的一个非正式定居点）的研究中，我们发现血浆赭曲霉毒素水平与促炎细胞因子和趋化因子水平之间存在很强的相关性。有趣的是，混合喂养（母乳中添加其他可能受霉菌毒素污染的食物）会使婴儿对艾滋病毒的易感性增加 11 倍。我将利用这一已知的艾滋病毒易感性差异来重点研究霉菌毒素引起的免疫变化。我们对卡耶利沙婴儿喂养方式的研究的初步结果显示，混合喂养婴儿的口腔粘膜中 CD4+ 免疫细胞群明显增多，这表明粘膜炎症可能在增加婴儿对艾滋病毒的易感性方面发挥着关键作用。这项研究将利用离体刺激和我们在 Khayelitsha 的婴儿喂养研究中的样本来研究霉菌毒素在口腔粘膜免疫调节中的作用。我假设接触霉菌毒素会诱导婴儿口腔粘膜产生趋化因子，优先招募 HIV 靶细胞，从而增加口腔粘膜对 HIV 的易感性。对霉菌毒素暴露的评估将重点关注 OTA、脱氧雪腐镰刀菌烯醇 (DON) 和伏马菌素 B1，这三种霉菌毒素已被反复证明可以调节体外和体内的免疫反应。对健康的、未暴露于霉菌毒素的成人和婴儿血液和口腔粘膜进行体外刺激，将用于定义口腔粘膜细胞响应霉菌毒素刺激而表达的趋化因子和趋化因子受体网络。卡耶利沙混合喂养婴儿的血液和口腔粘膜样本将用于阐明霉菌毒素暴露对南非婴儿免疫状态的影响。这些研究将结合转录组学、蛋白质组学、流式细胞术和细胞迁移测定，将其整合到基于系统生物学的计算分析和多变量分析中，以模拟趋化因子、细胞募集和先天免疫因子之间的复杂相互作用。上述工作将显着提高我们对食品污染物对发展中国家婴儿死亡率影响的了解。了解霉菌毒素在调节婴儿免疫系统中的作用并识别对婴儿健康影响最大的污染物将使资源有限的国家能够优先监管这些特定污染物，并可能导致识别影响婴儿发病率的其他环境免疫调节剂和发展中国家的死亡率。