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

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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.