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

描述（由申请人提供）：至少有200万南非人生活在非正式定居点，其中近20%的儿童在5岁之前死亡。欠发达地区的婴儿比发达国家的婴儿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被称为真菌毒素的真菌细胞毒性分子，这可能会增加感染的致病性。在南非开普敦外的一个非正式定居点Khayelitsha进行的研究中，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，即在母乳中补充其他可能被霉菌毒素污染的食物，会使婴儿对艾滋病毒的易感性增加多达11倍。我将利用这种已知的HIV易感性差异来集中研究真菌毒素引起的免疫变化。我们对Khayelitsha婴儿喂养实践的初步研究发现，混合喂养婴儿的口腔黏膜中CD4+免疫细胞群明显增加，这表明粘膜炎症可能在增加婴儿对艾滋病毒的易感性中起关键作用。本研究将研究真菌毒素在口腔黏膜免疫调节中的作用，采用体外刺激和来自卡耶利沙婴儿喂养研究的样本。我假设霉菌毒素暴露诱导婴儿口腔黏膜产生趋化因子，优先招募HIV靶细胞，增加口腔黏膜对HIV的易感性。真菌毒素暴露的评估将集中在OTA、脱氧雪腐镰刀菌醇（DON）和伏马菌素B1上，这三种真菌毒素已被反复证明可以调节体外和体内的免疫反应。对未接触真菌毒素的健康成人和婴儿血液和口腔黏膜进行体外刺激，将用于确定口腔黏膜细胞在真菌毒素刺激下表达的趋化因子和趋化因子受体网络。Khayelitsha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作用。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分析，并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复杂的相互作用。以上概述的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理解。了解真菌毒素在调节婴儿免疫系统中的作用和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调节这些特定污染物，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。

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.