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

University Of New Mexico, Albuquerque NM

Investigators

Abstract

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.