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

基本信息

  • 批准号:
    8811425
  • 负责人:
  • 金额:
    $ 3.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-02-15 至 2016-02-14
  • 项目状态:
    已结题

项目摘要

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.
至少有200万南非人生活在非正式定居点,近20%的儿童在5岁之前死亡。不发达社区的婴儿比发达国家的婴儿具有更高的基础免疫激活,这表明环境因素可能是造成这种高死亡率的原因。发展中国家的儿童经常接触真菌,细胞毒性分子,称为真菌毒素,可以增加感染的致病性。我们在南非的Khayelitsha(开普敦外的一个非正式定居点)进行的研究中发现,血浆赭曲霉素水平与促炎细胞因子和趋化因子水平之间存在强相关性。有趣的是,混合喂养,即母乳补充其他可能受霉菌毒素污染的食物,使婴儿对艾滋病毒的易感性增加了11倍。我将利用这种已知的HIV易感性差异来集中研究霉菌毒素诱导的免疫变化。我们对Khayelitsha婴儿喂养实践的研究的初步结果显示,混合喂养婴儿的口腔粘膜中CD4+免疫细胞群显着增加,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关键作用。本研究将调查真菌毒素在口腔粘膜免疫调节中的作用,使用离体刺激和我们在Khayelitsha进行的婴儿喂养研究的样本。我假设霉菌毒素暴露诱导婴儿口腔粘膜中趋化因子的产生,优先招募HIV靶细胞,增加口腔粘膜对HIV的易感性。真菌毒素暴露的评估将集中在OTA、脱氧雪腐镰刀菌烯醇(DON)和伏马菌素B1,这三种真菌毒素已被反复证明可调节体外和体内的免疫反应。将使用健康、未暴露于真菌毒素的成人和婴儿血液和口腔粘膜的离体刺激来确定口腔粘膜细胞对真菌毒素刺激的反应所表达的趋化因子和趋化因子受体的网络。来自Khayelitsha混合喂养婴儿的血液和口腔粘膜样本将用于阐明真菌毒素暴露对南非婴儿免疫状态的作用。这些研究将使用转录组学、蛋白质组学、流式细胞术和细胞迁移测定的组合,这些组合将被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。上述工作将大大提高我们对食品污染物对发展中国家婴儿死亡率影响的认识。了解真菌毒素在调节婴儿免疫系统中的作用,并确定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考虑对这些特定污染物的监管,并可能导致确定影响发展中国家婴儿发病率和死亡率的其他环境免疫调节剂。

项目成果

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Lianna F Wood其他文献

Lianna F Wood的其他文献

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{{ truncateString('Lianna F Wood', 18)}}的其他基金

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:
    8454135
  • 财政年份:
    2013
  • 资助金额:
    $ 3.7万
  • 项目类别:
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
  • 财政年份:
    2013
  • 资助金额:
    $ 3.7万
  • 项目类别:
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:
    8618783
  • 财政年份:
    2013
  • 资助金额:
    $ 3.7万
  • 项目类别:

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    1966
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