Nutrition and immunity in pregnancy: maternal responses and consequences for offspring

在怀孕期间，母亲的免疫系统面临着保护母亲和胎儿的任务。母亲依靠营养来维持她们的生理状况和免疫系统，也滋养她们发育中的后代。一个关键的问题是：当母亲面临生理状态的挑战时，她们如何分配能量来保护自己和后代？什么时候会导致不良后果，比如早产？迄今为止，大多数关于怀孕暴露的研究都涉及对人类的长期研究或对实验室啮齿动物或大型哺乳动物的实验。我们对怀孕期间的营养或感染如何影响出生时间和后代发育有了扎实的了解。很少有研究考虑到营养和感染之间的相互作用，这可能是由于所涉及的研究的规模和复杂性，或者是因为我们尚未建立一个明确的概念框架来提出关于这种相互作用的可测试的假设。在这里，我提出一个项目来解决这两个挑战：首先，在进化理论的指导下，建立一个关于怀孕期间营养和感染之间相互作用的正式框架，并使用昆虫怀孕模型来测试预测，同时分析来自对比人群的数据集。我将首先对人类和动物模型研究进行范围审查，以确定孕妇营养、病原体暴露和炎症反应之间的联系途径，以及对后代的影响。然后，我将开发数学模型来检验因果关系：在抵御病原体和滋养后代之间的能量权衡如何解释整个怀孕阶段的最佳免疫反应？这个正式的框架将为昆虫实验提供信息，昆虫实验非常适合研究充分的机制，包括在脊椎动物中发现的高度保守的免疫途径。大多数关于昆虫免疫的研究都集中在产卵的果蝇身上。我将使用经历怀孕的昆虫——采采蝇和太平洋甲虫蟑螂——对母体免疫反应和营养之间复杂的相互作用产生新的见解。这两个物种都表现出几乎哺乳动物的怀孕，用子宫内经过改造的器官产生的类似乳汁的物质来滋养它们的后代。与此同时，它们在进化上与不同的饮食相距甚远，因此为研究怀孕的特殊和一般机制提供了一个独特的机会。我会让孕妇直接接触到不同数量或质量的食物，或者间接激活她们的免疫系统。然后，我将测量母亲们的反应以及对她们的孩子的影响，包括出生时间、体型以及生理和基因表达的变化。最后，我将研究两项人类队列研究的模式，在不同的背景下：布里斯托尔地区的90年代儿童研究，饮食质量和报告的感染与母亲的社会经济地位一致，以及冈比亚西江农村地区的数据，资源匮乏，感染和食物供应具有强烈的季节性。我将比较怀孕不同阶段的感染对后代的影响，包括早产、儿童生长和后来的健康，以及这些影响如何随着母亲的营养状况而变化。该项目将提供基本的见解，了解母体营养和免疫反应如何相互作用，以决定怀孕结果和对后代的长期影响，跨越不同的生物。从长期来看，它还可以为改善出生结果的政策提供信息：例如，如果怀孕期间免疫激活导致早产风险增加，那么哪些营养干预措施可以降低这种风险？疫苗会产生轻微的免疫反应：如果在怀孕早期或晚期接种疫苗，对母亲和后代有什么风险？营养不足或营养过剩的母亲是否会有不同的风险？

During pregnancy, the mother's immune system faces the task of protecting both the mother and her foetus. Mothers rely on nutrients to maintain their physiological condition and immune system, and also to nourish their developing offspring. A key question is: when mothers face challenges to their physiological state, how do they allocate energy to protect themselves and their offspring? When does this result in adverse outcomes, such as pre-term birth?To date, most research on pregnancy exposures involves long-term studies in humans or experiments on laboratory rodents or larger mammals. We have a solid understanding of how nutrition or infections in pregnancy influence birth timing and offspring development. Remarkably few studies have considered the interaction between nutrition and infections, potentially owing to the scale and complexity of studies involved, or because we have yet to develop a clear conceptual framework to develop testable hypotheses about this interaction.Here, I propose a project which tackles these two challenges head on: first, to develop a formal framework on the interplay between nutrition and infection in pregnancy, informed by evolutionary theory, and to test predictions using insect models of pregnancy, in parallel with analysis of datasets from contrasting human populations. I will first conduct a scoping review of human and animal model studies to identify the pathways linking nutrition, pathogen exposure and inflammatory responses in pregnant mothers, and consequences for offspring. I will then develop mathematical models to examine causality: how do energy trade-offs between defending against pathogens or nourishing offspring explain the optimal immune response across pregnancy stages?This formal framework will inform experiments in insects, which are extremely amenable with well-studied mechanisms, including highly conserved immune pathways found in vertebrates. Most research on insect immunity has focused on egg-laying Drosophila. I will use insects which experience pregnancy - tsetse flies and Pacific beetle cockroaches - to yield new insights on the complex interplay between maternal immune responses and nutrition. Both species exhibit almost mammalian pregnancy, nourishing their young with a milk-like substance from modified organs in utero. At the same time, they are evolutionary distant with contrasting diets, thus providing a unique opportunity to study both the specific and general machineries of pregnancy. I will expose pregnant females on diets varying in quantity or quality directly to pathogens, or indirectly activate their immune system. I will then measure responses of mothers and consequences for their young, in terms birth timing, body size and changes in physiology and gene expression.Lastly, I will examine patterns in two human cohort studies, in divergent contexts: the Children of the 90s study in the Bristol region, where diet quality and reported infections align with maternal socio-economic status, and data from the rural West Kiang region in The Gambia, a low-resource setting with strong seasonality in infections and food availability. I will compare how infections at different stages of pregnancy affect offspring, in terms of pre-term birth, child growth and later health, and how such effects change with maternal nutritional state.This project will provide fundamental insights into how maternal nutrition and immune responses interact to determine pregnancy outcomes and longer-term consequences for offspring, across diverse organisms. In the longer term, it can also inform policy to improve birth outcomes: for example, if immune activation in pregnancy cause an increased risk of pre-term birth, what are the nutritional interventions that could reduce this risk? Vaccines result in a mild immune response: what are the risks to mothers and offspring if administered early or late in pregnancy, and do these vary between under- or over-nourished mothers?