Sensory and molecular studies of human taste dysfunction

Summary Project 3. Sensory and molecular studies of human taste dysfunction Taste dysfunction is a cardinal feature of COVID. Project 3 of this P50 Clinical Research Center (CRC) proposal focuses on (1) molecular description of taste tissue from people with sustained COVID-19-associated taste dysfunction, compared to people with no current taste problems (regardless of infection history) (Aim 3.1), and (2) mechanistic interrogation of COVID-associated taste dysfunction using taste organoids (Aim 3.2). We will test the hypothesis that people with COVID taste dysfunction have fewer taste receptor cells, reduced expression of taste-relevant genes, and immune cell infiltration due to sustained inflammation. In Aim 3.1, we will sample taste tissue from people with and without sustained COVID-19-associated taste dysfunction to measure taste receptor cell number and gene expression of inflammatory (e.g., cytokines and chemokines) and other molecules with single-cell RNA sequencing (scRNA-seq) methods. In Aim 3.2, we will use taste organoids derived from wild-type mice, humanized-ACE2 mice, and humans to examine SARS-CoV-2 tropism in taste tissue to determine if taste tissue homeostasis is altered by (a) SARS-CoV-2 infection or (b) inflammatory molecules identified in Aim 3.1 and/or known to be elevated in COVID. Project 3 of this CRC proposal is supported by Project 1 and the Chemosensory Clinical Services Core, which will perform and support remote and in-house sensory screening of all participants in this research program. The investigators here are experts in their fields, particularly in single-cell biology, genetics, and stem cell biology of taste tissue. We have engaged consultants who are inflammation, infection, and immunology experts. Several types of pilot data support this application, including scRNA-seq data from human fungiform tissue and taste organoid data after treatment with inflammatory molecules. Institutional support for this project is outlined in a Letter of Support from administrative officials, and the Monell Chemical Senses Center is well suited to complete this project because of its cross-disciplinary focus on chemosensory biology and its connection with an experienced coronavirus expert at the nearby University of Pennsylvania. This project is part of a larger program to understand and treat people with communication disorders of taste and smell dysfunction due to COVID. We anticipate our data will answer key unsolved questions regarding taste dysfunction and point to potential avenues of treatment for this debilitating condition.