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

进入大脑的门户：嗅觉隐窝神经元调节硬骨鱼的大脑病毒免疫

• 批准号: 1755348
• 负责人: Irene Salinas
• 金额: $ 55万
• 依托单位: University of New Mexico
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1755348&HistoricalAwards=false
• 关键词: portal; into; brain; olfactory; crypt

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.

神经系统和免疫系统之间的相互作用决定了动物与其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，如果神经元被病原体感染，它们也会产生自己的免疫反应。该项目的中心思想是，由于它们直接暴露于外部微生物，嗅觉感觉神经元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，这是鱼类所特有的。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播到鱼的中枢神经系统中的嗅球。因此，非常快速（几分钟内）的抗病毒免疫反应通过从嗅球迁移到鼻子的细胞在鼻上皮中建立。这项工作具有广泛的意义，包括对社会的影响，因为它将揭示硬骨鱼识别水中外部微生物信号的新机制。 对这一机制的理解在鱼类生物学和保护以及水产养殖和鱼类鼻疫苗开发领域具有影响。该项目的其他更广泛影响包括在新墨西哥州的农村学校开展外联活动，并举办讲习班，以扩大妇女对STEM学科的参与。嗅觉器官检测环境化学信号，并通过嗅球将其发送到中枢神经系统（CNS）。同时，嗅觉感觉神经元（OSN）与环境中存在的微生物（包括病毒）直接接触。硬骨鱼的嗅觉器官与哺乳动物相似，但它们有一种独特的OSN类型，称为隐窝神经元。隐窝神经元仅表达一种类型的嗅觉受体，ORA 4和酪氨酸激酶受体TrkA。虽然这个独特的OSN亚群的功能吸引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中隐窝神经元的新功能。核心假设是，隐窝神经元通过TrkA受体检测环境中的病毒，并监督CNS中的免疫反应，以避免炎症诱导的损伤。这一假设正在测试虹鳟鱼（虹鳟鱼）隐窝神经元暴露于鲑鱼病毒传染性造血坏死病毒（IHNV）。研究人员使用他们预先建立的鳟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CNS先天免疫反应，以及TrkA-病毒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片有助于阐明嗅觉器官和嗅球之间发生串扰的机制。这些发现将阐明一个重要的，但被忽视的神经免疫的相互作用，在硬骨鱼，中枢神经系统的免疫反应是精心策划从外围通过OSN electrical signals.This奖项反映了NSF的法定使命，并已被认为是值得支持的，通过评估使用基金会的智力价值和更广泛的影响审查标准。

项目成果

Neural circuits and olfactory responses to neurotropic viruses in trout.

鳟鱼对神经病毒的神经回路和嗅觉反应。

• 发表时间: 2019
• 期刊: The FASEB journal
• 作者: Mancha, F.;Salinas, I.;Huertas, M.
• 通讯作者: Huertas, M.

Comparative models for human nasal infections and immunity

• DOI: 10.1016/j.dci.2018.11.022
• 发表时间: 2019-03-01
• 期刊: DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY
• 影响因子: 2.9
• 作者: Casadei, Elisa;Salinas, Irene
• 通讯作者: Salinas, Irene

Innate-like CD8 T cells in the teleost olfactory-CNS axis express NK cell markers and mount rapid polyclonal responses to viral antigens

硬骨鱼嗅觉中枢神经系统轴中的先天性 CD8 T 细胞表达 NK 细胞标记并对病毒抗原产生快速多克隆反应

• 发表时间: 2020
• 期刊: The journal of immunology
• 作者: Irene Salinas, Pankoj Kumar

Fish nasal immunity: From mucosal vaccines to neuroimmunology

• DOI: 10.1016/j.fsi.2020.05.076
• 发表时间: 2020-09-01
• 期刊: FISH & SHELLFISH IMMUNOLOGY
• 影响因子: 4.7
• 作者: Das, Pankoj Kumar;Salinas, Irene
• 通讯作者: Salinas, Irene