Defining mucosal plasma cell origin, residence, and longevity in the upper airway

The upper respiratory tract is lined by two distinct mucosal tissues. Respiratory mucosa humidifies and modulates incoming air temperature as it passes toward the lungs. Olfactory mucosa on the other hand is specialized for chemosensation and supports detection of airborne odorants by olfactory sensory neurons (OSNs). We have recently described an endothelial level barrier, a “blood-olfactory barrier” (BOB), that prevents high molecular weight proteins like antibodies (~150kD) from accessing the olfactory mucosa. Antibodies are absolutely required to prevent olfactory reinfection by airway viral infections, but serum neutralizing antibody provides no protection. Our studies have found that antibody secreting plasma cells (PCs) must reside within olfactory tissues- beyond the BOB- to provide locally neutralizing antibody in order to prevent olfactory infection. While vaccines generate robust circulating antibody titers, we found that they generally fail to differentiate OlfPC and as such, fail to protect against olfactotropic pathogens (that infect the olfactory mucosa), including SARS-Cov-2. Tissue specific PCs are generally understudied and this proposal will specifically establish a foundational understanding of when OlfPCs establish tissue residence, how long and where they reside within olfactory tissues, and how these cells relate to the peripheral BM PC pool. These data will empower mechanistic improvements to vaccines against upper respiratory infection.