Impact of HIV exposure, feeding status, and microbiome on immune ontogeny and vaccine responses in infants

项目摘要 每年约有800万5岁以下儿童死亡，其中约330万人 死亡发生在新生儿期。感染是导致这些死亡的最大原因， 估计有36%的死亡率然而，我们对新生儿和婴儿免疫系统如何 这种对传染病的易感性是有限的。因此，为了阐明调节 婴儿免疫力的发展，我们建议在高风险的环境中评估免疫发育， 新生儿和婴儿感染。特别是，接触艾滋病毒但未受感染的婴儿， 呼吸道和呼吸道疾病发病率增加。进食状态也与以下风险的改变有关： 全母乳喂养的儿童不太可能患疟疾和死亡。我们的初步 数据表明，艾滋病毒暴露和喂养状况都会影响婴儿的微生物组， 因其在推动免疫发育中的重要作用而受到认可。因此，为了更好地了解独特的 在新生儿和婴儿的免疫发育特点，我们建议评估艾滋病毒的影响， 暴露和喂养状况对微生物组、先天性和适应性细胞免疫之间相互作用的影响 个体发育和疫苗接种结果。我们的初步数据还表明，艾滋病毒暴露导致 T细胞库中的寡克隆性，潜在地缩小了婴儿T细胞可以识别的抗原谱。 回答。我们还发现，艾滋病毒感染增加自然杀伤（NK）细胞的多样性，同时减少NK 细胞毒功能使用从艾滋病毒暴露的未感染者和艾滋病毒感染者中收集的纵向样本， 在南非艾滋病毒感染率极高的地区，我们将：1）比较T 和NK细胞库和功能之间的HEU和HU婴儿，2）确定母亲艾滋病毒的影响， 喂养状态、肠道和母乳微生物组对婴儿粘膜微生物组的影响，以及3）建立预测性 有效百日咳和轮状病毒疫苗模型，以确定与疫苗相关的主要因素 成功或失败这项研究将提供一个全面的了解如何细胞免疫反应 微生物组在生命的第一年进化，并影响产生有效细胞的能力， 体液免疫反应。

PROJECT SUMMARY Each year, approximately 8 million children under the age of five die, and approximately 3.3 million of those deaths occur in the neonatal period. Infections are the single largest contributor to these deaths, accounting for an estimated 36% of the mortality. However, our understanding of how the neonatal and infant immune system influence this susceptibility to infectious diseases is limited. Thus, to elucidate mechanisms that regulate the development of infant immunity, we propose evaluating immune development in a setting of high risk of neonatal and infant infection. In particular, infants who are exposed to HIV, yet remain uninfected, suffer increased rates of respiratory and diarrheal illnesses. Feeding status is also associated with altered risk of infection, with exclusively breastfed children less likely to suffer diarrheal illness and death. Our preliminary data suggest that both HIV exposure and feeding status influence the infant microbiome, which is increasingly recognized for its important role in driving immune development. Thus, to better understand the unique characteristics of immune development in neonates and infants, we propose evaluating the impact of HIV exposure and feeding status on the interplay between the microbiome, innate and adaptive cellular immune ontogeny, and vaccination outcomes. Our preliminary data also suggests that HIV exposure leads to oligoclonality in the T cell repertoire, potentially narrowing the spectrum of antigens to which infant T cells can respond. We have also found that HIV infection increases natural killer (NK) cell diversity while decreasing NK cell cytotoxic function. Using longitudinal samples collected from HIV-exposed uninfected (HEU) and HIV- unexposed (HU) babies in an area of extremely high HIV prevalence in South Africa, we will: 1) compare the T and NK cell repertoires and function between HEU and HU babies, 2) determine the impact of maternal HIV, feeding status, gut and breastmilk microbiome on the infant mucosal microbiome, and 3) build a predictive model of effective pertussis and rotavirus vaccines to identify the major factors that associate with vaccine success or failure. This study will provide a comprehensive understanding of how cellular immune responses and the microbiome evolve in the first year of life and influence the ability to generate an effective cellular and humoral immune responses.