Mechanisms of Long-term Taste Loss in Post-Acute Sequelae of COVID-19

Introduction: A substantial proportion of COVID-19 patients experience taste dysfunction. While taste loss is temporary for many, approximately 5-10% develop long-term deficits lasting more than 6 months, which can negatively impact quality of life and contribute to anxiety and depression. This study focuses on long-term taste loss following COVID-19.

Objective: The overall objective is to investigate the underlying mechanisms of post-COVID-19 taste loss, with particular emphasis on the roles of antiviral pathways and inflammatory cytokines.

Methods: This study has two specific aims: Aim 1 investigates whether deficiencies in antiviral pathways contribute to excessive taste tissue damage and inflammation. We use humanized mice (human ACE2-knockin) with or without key antiviral genes (IRF3 or IFNAR1). The goal is to compare the severity of taste tissue injury in wild-type mice versus mice lacking IRF3 or IFNAR1. Aim 2 investigates whether inflammatory cytokines inhibit taste bud regeneration. Taste tissue stem cells normally generate new taste cells throughout the lifespan; however, impaired regeneration may underlie long-term taste loss. Here we use an in vitro taste organoid culture system to test and screen inflammatory cytokines for their effects on taste cell regeneration.

Results: Our main findings are as follows: 1.) Mice lacking functional IRF3 or IFNAR1 exhibited higher viral RNA levels in taste tissues, indicating that SARS-CoV-2 replicates more readily in the absence of these antiviral pathways. 2.) The number of gustatory nerve fibers innervating taste buds was reduced in IFNAR1-knockout mice following SARS-CoV-2 infection. 3.) The inflammatory cytokines interferon-γ and tumor necrosis factor significantly impaired taste cell generation in the organoid model, either by inducing cell death or by inhibiting cell differentiation.

Conclusion/Discussion: Together, our results suggest that patients with defects in the IRF3 or IFNAR1 pathways are at increased risk for developing long-term taste loss after COVID-19, and that interferon-γ and tumor necrosis factor may contribute to impaired taste bud regeneration following viral infection.

Key Topics:

• Advanced imaging analysis to define the long term impact of COVID on organ structure/function and characterize Long COVID phenotypes
• Assay and in vitro studies to gain mechanistic insights
• Chronic immune dysfunction
• Developing models of similar diseases/syndrome
• Long COVID and other chronic conditions
• Long COVID in special populations,Nonhuman primate (NHP) and/or other animal models
• Remaining gaps in tissue-specific manifestations of Long COVID