Pre- and post-natal programming of the neuroendocrine-immune system: Implications for stress resilience, disease resistance, and longevity

畜牧和水产养殖物种经常受到不同类型的压力，如微生物感染。神经内分泌免疫（NEI）系统在启动和调节宿主对应激源的反应中起着核心作用，并有助于在应激事件过去后恢复生理平衡。发育中的NEI系统对产前和产后压力（PPS）非常敏感，当在发育的某些窗口期间经历PPS时，NEI系统的遗传编程可能会受到永久性影响。有人提出，这种NEI可塑性是一种适应机制，有助于新生动物为新环境做好准备;然而，如果NEI编程与出生后环境不匹配，它可能会对后代的压力恢复力、抗病能力和寿命产生负面影响;所有这些都是加拿大畜牧业和水产养殖业（CLAS）重要的健康、福利和经济问题。人类研究表明，压力诱导的发育编程的影响可以在几代人之间表现出来，性别特异性反应很常见;但这对CLAS的影响目前尚不清楚。研究人员历来专注于母亲和新生儿的压力;然而，父亲的压力似乎同样重要。NEI系统编程发生的作用机制（MOAs）刚刚开始被理解，并且似乎涉及影响基因调控的表观遗传学变化。* 在这一研究领域中，大型动物研究的一个主要局限性是，它们进行起来极其昂贵和耗时，特别是在研究世代、父母和性别影响以及MOA时。我们相信，斑马鱼（Zf）是一种成熟的人类生理学和疾病模型，有可能大大推进这一领域的CLAS研究。在该提案中，我们计划使用细菌脂多糖（LPS）内毒素免疫刺激（BEIS）开发Zf PPS模型; LPS构成革兰氏阴性菌（如大肠杆菌）的细胞膜，通常用于研究模拟细菌感染。然后，这些PPS模型将用于评估BEIS应激后的幼虫和新生儿NEI编程，包括MOA。由于鱼类缺乏哺乳动物所拥有的主要LPS受体Toll样受体4，因此鉴定能够识别LPS的受体将是重要的;这些受体可以作为营养和疫苗诱导的先天免疫刺激的替代靶标，并且可能在物种间具有多态性，这对于遗传选择很重要。这项研究将帮助我们更好地了解PPS对发育中动物的长期影响，并使我们能够研究调节过程，以增强CLAS中饲养的动物的整体应激能力，抗病能力和寿命，而无需依赖抗菌剂来预防新生儿疾病。

Livestock and aquaculture species are often subjected to different types of stressors, like microbial infections. The neuroendocrine-immune (NEI) system plays a central role in mounting and regulating the host response to stressors, and helps restore physiological balance after a stress event has passed. The developing NEI system is very sensitive to prenatal and postnatal stress (PPS), and when PPS is experienced during certain windows of development, genetic programming of the NEI system can be permanently affected. It has been proposed that this NEI malleability is an adaptive mechanism that helps newborn animals prepare for their novel environment; however, if NEI programming is mismatched to the postnatal environment, it can negatively impact offspring stress resilience, disease resistance, and longevity; all of which are important health, welfare and economic concerns for the Canadian livestock and aquaculture sectors (CLASs). Human studies, have shown the effects of stress-induced developmental programming can manifest across generations, and sex-specific responses are common; but the impact of this on the CLASs is currently unknown. Researchers have historically focused on maternal and neonatal stress; however, paternal stress appears to be equally important. The mechanisms of action (MOAs) by which NEI system programming occurs are just beginning to be understood, and appear to involve epigenetics changes affecting gene regulation. ***A major limitation of large animal studies in this research area is that they are extremely costly and time consuming to conduct, especially when generational, parental and sex effects, and MOAs are investigated. We believe the zebrafish (Zf), which is a well-established model of human physiology and disease, has the potential to greatly advance CLASs research in this area. In this proposal, we plan to develop Zf PPS models using bacterial lipopolysaccharide (LPS) endotoxin immune stimulation (BEIS); LPS makes up the cell membrane of Gram-negative bacteria such as Escherichia coli, and is commonly used in research to simulate a bacterial infection. These PPS models will then be used to assess larval and neonatal NEI programming, including MOAs, following BEIS stress. Since fish lack the main LPS receptor possessed by mammals, Toll-like receptor 4, it will be important to identify receptors that enable LPS recognition; these can serve as alternative targets for nutrition- and vaccine-induced innate immune stimulation, and may be polymorphic across species, which is important for genetic selection. This research will help us to better understand the long-term impact of PPS on developing animals, and will allow us to investigate regulatory processes may be modulated to enhance overall stress resilience, disease resistance, and longevity of animals reared in the CLASs without relying on antimicrobials to prevent neonatal disease.