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

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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?