COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters.

Charlotte Hautefort ,Lauriane Kergoat ,Florence Larrous ,C. Aparicio ,Étienne Kornobis ,Flora Donati ,Dominique Salmon ,Pierre−Marie Lledo ,Vincent Michel ,Marc Lecuit ,Rémi Hervochon ,Guilherme Dias De Melo ,Gilles Gheusi ,Emmanuel Roze ,Sébastien Wagner ,Yoann Madec ,Thomas Cokelaer ,Hervé Bourhy ,Sylvain Levallois ,Françoise Lazarini ,Benjamin Vérillaud

doi:10.1126/scitranslmed.abf8396

Abstract

Whereas recent investigations have revealed viral, inflammatory, and vascular factors involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lung pathogenesis, the pathophysiology of neurological disorders in coronavirus disease 2019 (COVID-19) remains poorly understood. Olfactory and taste dysfunction are common in COVID-19, especially in mildly symptomatic patients. Here, we conducted a virologic, molecular, and cellular study of the olfactory neuroepithelium of seven patients with COVID-19 presenting with acute loss of smell. We report evidence that the olfactory neuroepithelium is a major site of SARS-CoV2 infection with multiple cell types, including olfactory sensory neurons, support cells, and immune cells, becoming infected. SARS-CoV-2 replication in the olfactory neuroepithelium was associated with local inflammation. Furthermore, we showed that SARS-CoV-2 induced acute anosmia and ageusia in golden Syrian hamsters, lasting as long as the virus remained in the olfactory epithelium and the olfactory bulb. Last, olfactory mucosa sampling from patients showing long-term persistence of COVID-19-associated anosmia revealed the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation. SARS-CoV-2 persistence and associated inflammation in the olfactory neuroepithelium may account for prolonged or relapsing symptoms of COVID-19, such as loss of smell, which should be considered for optimal medical management of this disease.

Highlights

COVID-19, caused by SARS-CoV-2 commonly induces airway and pulmonary symptoms, and in severe cases leads to respiratory distress and death [1]
By combining investigations of COVID-19-associated olfactory function loss in patients and experimentally-infected hamsters, both naturally permissive to SARS-CoV-2 infection, we demonstrate that multiple cell types of the olfactory neuroepithelium are infected during the acute phase, at the time when loss of smell manifests, and that protracted viral infection and inflammation in the olfactory neuroepithelium may account for prolonged hyposmia/anosmia
Olfactory mucosa cytological sampling collected from acute or chronically patients with COVID-19 with olfactory function loss revealed the presence of the SARS-CoV-2 in 100% of patients (n=11) whereas the virus was undetected by RT-qPCR performed at inclusion on conventional nasopharyngeal swabs

Summary

Introduction

COVID-19, caused by SARS-CoV-2 commonly induces airway and pulmonary symptoms, and in severe cases leads to respiratory distress and death [1]. A sudden loss of olfactory function in SARS-CoV-2-infected individuals was reported worldwide at the onset of the pandemic. Loss of smell (anosmia) and/or of taste (ageusia) are considered as cardinal symptoms of COVID-19 [2,3,4]. A wide range of central and peripheral neurological manifestations have been observed in severe patients. Neuropilin-1 was found to facilitate SARS-CoV-2 entry in neural cells [5], and a neurotropism of SARS-CoV-2 could be suspected, a direct role of the virus in the neurological manifestations remains highly debated [2, 6]

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