Inflammation-based persistent smell and taste dysfunction across development

Summary. Project 1. Inflammation-based persistent smell and taste dysfunction across development. Chemosensory dysfunction (CD), including loss of smell and taste, has been linked to poor mental health, diet quality, and chronic diseases such as obesity and hypertension, as evidenced by national representative studies and patient experiences. Treating these conditions costs taxpayers billions annually. The COVID pandemic has exacerbated the issue, with millions more Americans experiencing persistent CD and an increased risk of chronic diseases. One hypothesis suggests that inflammation processes persist after SARS- CoV-2 infection and contributes to long COVID, but risk factors for persistent dysfunction and the impact of inflammation on recovery remain unclear. To address these gaps, we propose to characterize N = 900 individuals, ages 5 to 99, with and without persistent dysfunction in long COVID, following N = 200 for 4 years. We will create norms for comprehensive chemosensory profiles (smell, taste, retronasal olfaction, and chemesthesis, Aim 1.1) and identify nasal and oral inflammation biobehavioral markers in each group (Aim 1.2). We will develop a model to predict recovery patterns (Aim 1.3), including the relationships among chemosensation, inflammation, cognitive functioning, and other long-COVID symptoms. Participants will be compared based on sustained CD versus those who never lost or returned to normal function at the time of testing, confirmed by psychophysical tests. This proposal includes expertise from (i) Project Lead Parma, Assistant Director of Monell, founding Chair of the Global Consortium for Chemosensory Research, expert in COVID-related CD and chemosensory-related cognitive and emotional sequelae and experienced in handling rapidly changing, large research projects; (ii) Project Lead Dalton, Member of Monell, internationally recognized chemosensory scientist expert in how cognitive and emotional processes modify chemosensory perception, including chemosensory irritation, markers of chemical exposure, and leading developer of smell tests to be used across development; (iii) Co-I Wang, Member of Monell, world-renowned chemosensory immunologist; (iv) Co-I Zhao, expert chemosensory scientist who will lead data collection at a site with a long- COVID clinic; and (v) Co-I Ho, expert in data analysis for cognitive, sensory, and quality-of-life endpoints, part of the developing team of the NIH Toolbox®. This team has a strong collaborative history and meets weekly to prepare this application. This project will significantly advance the understanding of persistent smell and taste dysfunction, particularly in the context of inflammation related to long COVID, across different age groups. By providing mechanistic insights and identifying individual variability in recovery paths, it supports the NIDCD 2023-2027 strategic plan, promoting precision medicine and basic research to understand health and disease.