Collaborative Research: IntBIO: The Evolution of Immune Investment Strategies Across Amphibian Ontogeny

人类和动物中新发传染病的频率越来越高，这突出表明需要更好地了解生物体为抵御这些感染而部署的免疫防御机制。值得注意的是，免疫系统对抗感染的能力随着生物体从出生到老年的发展而变化。毕竟，遇到病原体的风险与年龄相关的行为和环境有关，过度强烈的免疫反应会消耗宝贵的能量，引发自身免疫性疾病。因此，不同年龄的生物体可能从相同类型的免疫反应中获得不均衡的益处。基于对蛙（Xenopus laevis）蝌蚪包含的适应性T细胞比成年青蛙的适应性T细胞多样性更少，而更多地依赖于先天样T细胞的观察，本项目的目的是研究影响T细胞免疫变化的生态和进化因素，因为一个生物体从年轻到年老的生命阶段。为了实现这一目标，该项目将整合免疫学、进化生物学和数学领域的方法，研究目前全球范围内受到致命真菌病原体威胁的两栖动物物种的T细胞受体多样性。该项目将为不同群体的早期职业科学家提供培训，并促进主动学习模块的开发，通过青蛙生物学的视角向学生传授免疫系统知识。青蛙是研究先天样T细胞和适应性T细胞年龄结构投资的最佳系统，因为它们在生活史上具有高度的多样性和对突发病原体的易感性。项目的三个目标是：(1)利用数学模型和经验数据来预测进化史、病原体和环境在生态和进化时间尺度上对生命阶段内和生命阶段间T细胞多样性有利的时间；(2)利用RACE-PCR和RNA-seq来量化跨越青蛙生命树和已知蝌蚪发育时间的多种青蛙物种的T细胞受体多样性；(3)在实验室环境中通过实验控制早期饮食和环境，量化发育可塑性对青蛙T细胞受体多样性和感染结果的影响程度。本研究将经典免疫学技术与进化遗传学、数学建模、实验室实验和自然种群抽样相结合，对驱动免疫系统成熟、可塑性和多样性进化的因素产生前所未有的见解。同时，该项目将培养跨学科免疫学的年轻科学家，从而有助于形成对免疫反应感兴趣的下一代科学家。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The increasing frequency of emerging infectious diseases in humans and animals underscores the need to better understand the immune defenses that organisms deploy to ward off these infections. Notably, the ability of the immune system to fight infection changes as an organism progresses from birth to old age. After all, the risk of encountering pathogens is tied to age-related behaviors and environmental setting, and overly strong immune responses can drain precious energy and fuel autoimmune diseases. As a result, organisms of different ages may derive uneven benefits from the same types of immune responses. Building on the observation that frog (Xenopus laevis) tadpoles contain a less diverse set of adaptive T cells than those of adult frogs and instead rely more on innate-like T cells, the purpose of this project is to investigate the ecological and evolutionary factors that influence changes in T cell immunity as an organism proceeds from younger to older stages of its life. To accomplish this, the project will integrate approaches from the fields of immunology, evolutionary biology and mathematics to investigate T cell receptor diversity across amphibian species currently under existential threat worldwide from a deadly fungal pathogen. The project will provide training to a diverse group of early career scientists and spur the development of active learning modules to educate students about the immune system through the lens of frog biology. Frogs represent an optimal system to investigate age-structured investment in innate-like and adaptive T cells because of their high diversity in life histories and susceptibility to emergent pathogens. The three project objectives are to: (1) use mathematical models and empirical data to predict when evolutionary history, pathogens, and environment favor T cell diversity within and among life stages on ecological and evolutionary time scales, (2) use RACE-PCR and RNA-seq to quantify T cell receptor diversity for multiple frog species spanning the frog tree of life and known tadpole development times, and (3) experimentally manipulate early-life diet and environment in a laboratory setting to quantify the extent of developmental plasticity on frog T cell receptor diversity and infection outcomes. This proposal integrates classic immunological techniques with evolutionary genetics, mathematical modeling, lab experimentation, and natural population sampling to yield unprecedented insights into the factors that drive the evolution of immune system maturation, plasticity, and diversity. At the same time, this project will train young scientists in interdisciplinary immunology, thus contributing to the formation of the next generation of scientists with interest in immune responses.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.