A portal into the brain: olfactory crypt neurons modulate brain viral immunity in teleost

神经系统和免疫系统之间的相互作用决定了动物与环境之间的相互作用，从而决定了任何动物物种的生存和成功。以前的工作已经证明，神经元可以调节免疫反应，如果神经元受到病原体的感染，它们也会启动自己的免疫反应。该项目的中心思想是，由于嗅觉感觉神经元直接接触外部微生物，它们能够通过使用电信号以非常快速的方式感知感染并启动免疫反应。这项工作集中在一种类型的嗅觉感觉神经元-隐窝神经元，这是鱼类特有的。正在测试的假设是，通过表达酪氨酸激酶受体，隐窝神经元与鱼类病毒中存在的蛋白质相互作用。这种相互作用导致神经元电信号快速传递到鱼的中枢神经系统的嗅球。因此，通过从嗅球迁移到鼻子的细胞，很快(在几分钟内)抗病毒免疫反应就会安装在鼻黏膜上皮细胞中。这项工作具有广泛的意义，包括对社会的影响，因为它将揭示一种新的机制，通过这种机制，硬骨鱼可以识别水中的外部微生物信号。对这一机制的了解对鱼类生物学和养护以及水产养殖和鱼类鼻腔疫苗的开发都有影响。该项目的其他更广泛的影响包括扩展到新墨西哥州的农村学校和讲习班，以扩大妇女参与STEM学科的范围。嗅觉器官探测环境化学信号，并通过嗅球将它们发送到中枢神经系统。与此同时，嗅觉神经元(OSN)与环境中存在的微生物(包括病毒)直接接触。硬骨鱼的嗅觉器官类似于哺乳动物的嗅觉器官，但它们有一种独特的OSN类型，称为隐窝神经元。隐窝神经元只表达一种类型的嗅觉受体ORA4和酪氨酸激酶受体TrkA。尽管这个独特的OSN亚群的功能已经引起了许多研究人员的注意，但隐窝细胞的功能仍然是一个谜。这个项目的目标是测试硬骨鱼隐窝神经元的一种新功能。中心假设是隐窝神经元通过TrkA受体检测环境中的病毒，并监督中枢神经系统的免疫反应，以避免炎症诱导的损伤。这一假说正在暴露于鲑鱼病毒感染性造血坏死病毒(IHNV)的虹鳟鱼(Oncorhynchus Mykis)隐窝神经元中进行测试。研究人员使用他们预先建立的鲑鱼体内模型以及药理学和分子方法来确定隐窝神经元如何调节中枢神经系统的先天性免疫反应，以及TrkA与病毒的相互作用如何在这一过程中发挥作用。此外，电生理方法和神经切割法有助于阐明嗅觉器官和嗅球之间产生串扰的机制。这些发现将阐明硬骨鱼中一种重要但被忽视的神经免疫相互作用，通过OSN电信号从外围协调中枢神经系统免疫反应。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The interactions between the nervous system and the immune system determine the interactions between animals and their environment and, therefore, the survival and success of any animal species. Previous work has demonstrated that neurons can regulate immune responses, and that if neurons are infected with pathogens, they will also mount their own immune responses. The central idea of this project is that, given their direct exposure to external microorganisms, olfactory sensory neurons are able to sense infection and initiate immune responses in very rapid ways, by using electrical signals. The work focuses on one type of olfactory sensory neuron, the crypt neuron, which is unique to fishes. The hypothesis being tested is that by expressing a tyrosine kinase receptor, crypt neurons interact with proteins present in fish viruses. This interaction results in neuronal electrical signals that travel fast to the olfactory bulb in the central nervous system of the fish. Consequently, very fast (within minutes) antiviral immune responses are mounted in the nasal epithelium via cells that migrate from the olfactory bulb to the nose. The work has broad implications, including for society, because it will reveal a new mechanism by which bony fish recognize external microbial signals in the water. Understanding of this mechanism has impacts in the field of fish biology and conservation as well as aquaculture and nasal vaccine development for fish. Additional broader impacts of this project include outreach to rural schools in New Mexico and workshops to broaden participation of women in STEM disciplines.Olfactory organs detect environmental chemical signals and send them to the central nervous system (CNS) via the olfactory bulb. At the same time, olfactory sensory neurons (OSNs) are in direct contact with microorganisms present in the environment including viruses. Teleost fish have olfactory organs that resemble those of mammals, yet they have a unique type of OSN named crypt neurons. Crypt neurons express only one type of olfactory receptor, ORA4, and the tyrosine kinase receptor TrkA. Although the function of this unique OSN subset has attracted the attention of many investigators, crypt cell function remains a mystery. The goal of this project is to test a new function for crypt neurons in teleost fish. The central hypothesis is that crypt neurons detect viruses in the environment via the TrkA receptor and oversee immune responses in the CNS to avoid inflammation-induced damage. This hypothesis is being tested in rainbow trout (Oncorhynchus mykiss) crypt neurons exposed to the salmonid virus infectious hematopoietic necrosis virus (IHNV). The investigators use their pre-established trout in vivo model and pharmacological and molecular approaches to determine how crypt neurons modulate CNS innate immune responses, as well as how TrkA-viral interactions play a role in this process. Additionally, electrophysiological approaches and nerve sectioning serve to shed light on the mechanisms by which the cross-talk between the olfactory organ and the olfactory bulb occurs. The findings will elucidate an important but overlooked neuroimmune interaction in teleosts by which CNS immune responses are orchestrated from the periphery via OSN electrical signals.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.