Deciphering the Mechanisms of COVID-19 Induced Anosmia

SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (OR) and of their signaling components. This non-cell autonomous effect coincides with a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic OR compartments and elimination of genomic contact domains genomewide. Our data provide a novel mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, providing insight to its systemic effects in the nervous system and beyond. Funding Information: NIDCD 3R01DC018744-01S1 (SL, JO) National Institutes of Health grant, 4D Nucleome Consortium U01DA052783 (SL) Howard Hughes Medical Institute Faculty Scholar Award (SL), Zegar Family Foundation (SL). Ethics Approval Statement: The study was approved by the ethics and Institutional Review Board of Columbia University Medical Center (IRB AAAT0689, AAAS7370). LVG Golden Syrian hamsters (Mesocricetus auratus) were treated in compliance with the rules and regulations of IACUC under protocol number PROTO202000113-20-0743.