Complex Odor Recognition of the Main Olfactory Bulb

PROJECT SUMMARYCOVID-19 is a devastating disease caused by the severe acute respiratory syndrome coronavirus clade 2(SARS-CoV2) that has resulted in 100,442 deaths in the U.S. (May 28th, 2020). Smell loss is a major symptomfor COVID-19 (1-4). In a recent publication we identified TRPM5-expressing cells (microvillous cells (MVCs)and olfactory sensory neurons (OSNs)) as viral-responding cells in the olfactory epithelium (OE)(5). MVCs arepart of a family of TRPM5-expressing cells found in the airways and the intestine that respond to virus, bacteriaand irritants with a type 2 immune response through IL-25 and release of acetylcholine (6, 7). In preliminarystudies we find that intranasal herpes simplex virus type 1 (HSV-1) infection in mice elicits a dramatic shift inTRPM5 expression from MVCs to the basal epithelium consistent with activation of stem cells (SCs) forimmune defense, as proposed for chronic inflammation of the OE (8-10)expressionHowever,inflammationIt is unclear whether this increasedand altered location of TRPM5 is an aberrant response, contributing to persistent inflammation.influenza infection increases TRPM5 expressing cells in the lung, leading to damaging persistent(11) Here.. we hypothesize that SARS-CoV-2 infection of OE upregulates TRPM5expression, leading to proinflammatory cytokine release, decrease in OSN numbers and activity,persistent inflammation yet ineffective viral clearance leading to worse COVID-19; whereas addition ofTRPM5 blockers will attenuate cytokine release and viral loads.Weepithelialflufenamicwill test this hypothesis with studies of changes in inflammation and olfactory function in human olfactorycell cultures infected with by inhibition of TRPM5 using the FDA approved drugacid in two specific aims:SARS-CoV2Aim 1. Determine if activation of the TRPM5 transduction cascade in MVCs mediates the inflammatoryresponse to SARS-CoV-2 viral infection leading to loss of olfactory function.Aim 2. Determine if TRPM5 expression in the OE promotes SARS-CoV-2 neurotropism, facilitatingnervous system disease.