Defining the molecular and anatomical basis of the blood-olfactory barrier (BOB)

上呼吸道内衬有两种不同类型的上皮。呼吸道上皮加湿， 调节进入肺部的空气温度。另一方面，嗅觉上皮是 专门用于化学感觉，并支持嗅觉感觉神经元检测空气中的气味 （OSN）。我们最近描述了嗅粘膜内的血管形成了一个“血嗅区”， 嗅觉屏障（BOB），其防止高分子量血液传播蛋白质进入嗅觉组织。 这种BOB有效地将嗅觉组织与血液传播的分子隔离开来，其方式与 血脑屏障和血视网膜屏障在大脑和眼睛中起作用。在我们的研究中，我们发现， 针对病毒病原体的抗体（~ 150 kD）不能离开血液以防止嗅觉内的感染 上皮BOB的存在可能有助于调和多年来看似矛盾的上呼吸道 免疫数据，也有助于解释为什么病原体，如SARS-CoV-2，感染嗅觉上皮 当血液抗体滴度很高时会引起“突破性感染”。我们对基本的 这种新定义的血管屏障的细胞和分子构建块。该提案将建立 BOB稳态渗透性的限制和关于BOB的几个基本见解，包括： 从发育阶段到成年后期的功能，决定了细胞和连接组成， 产生BOB，定义健康和炎症期间的功能渗透性限制， 确定嗅觉神经元在协调嗅觉屏障身份中的作用。

The upper respiratory tract is lined by two distinct types of epithelium. Respiratory epithelium humidifies and modulates incoming air temperature as it passes toward the lungs. Olfactory epithelium on the other hand is specialized for chemosensation and supports detection of airborne odorants by olfactory sensory neurons (OSNs). We have recently described that blood vessels within the olfactory mucosa form a “blood -olfactory barrier” (BOB) that prevents high molecular weight blood borne proteins from accessing the olfactory tissues. This BOB effectively isolates olfactory tissues from blood borne molecules in much the same way that the blood brain barrier and the blood retinal barrier function in the brain and eye. In our studies we found that antibodies (~150kD) against viral pathogens cannot exit the blood to prevent infections within the olfactory epithelium. The existence of the BOB may help reconcile years of seemingly contradictory upper airway immunity data, and also helps explain why pathogens such as SARS-CoV-2 that infect the olfactory epithelium cause “breakthrough infections” when blood antibody titers are high. We know very little about the basic cellular and molecular building blocks of this newly defined vascular barrier. This proposal will establish the limits of BOB homeostatic permeability and several foundational insights about the BOB, including: BOB functionality from developmental stages until late adulthood, determine the cellular and junctional makeup that generates the BOB, define the functional permeability limits during health and inflammation, and finally determine the role of olfactory neurons in orchestrating olfactory barrier identity.