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

Abstract

Whereas recent investigations have revealed viral, inflammatory and vascular factors involved in SARS-CoV-2 lung pathogenesis, the pathophysiology of neurological disorders in 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 may be 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. Finally, 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.

Comparison of Brain Activation Patterns during Olfactory Stimuli between Recovered COVID-19 Patients and Healthy Controls: A Functional Near-Infrared Spectroscopy (fNIRS) Study

“…Reduced SIT-12 scores in this sample of patients is consistent with previous studies that reported a persistent loss of smell even after patients with this symptom recovered from COVID-19 infection [38,39]. The cellular basis for these observations may be explained by a study describing the presence of virus transcripts and of SARS-CoV-2-infected cells in the olfactory mucosa of patients with long-term persistence of COVID-19-associated loss of smell [40].…”

Auditory Disturbances and SARS-CoV-2 Infection: Brain Inflammation or Cochlear Affection? Systematic Review and Discussion of Potential Pathogenesis

“…Several studies have described the presence of brain lesions as responsible of auditory impairment (9)(10)(11), supporting the hypothesis that SARS-CoV-2, which has neuro-invasive characteristics, might determine a central hearing loss in COVID-19 patients both in the active phase and during recovery (12). It has been shown that the virus can spread from neuroepithelium to the olfactory bulb to the brain (13)(14)(15), causing loss of smell (16), persistent cough after pneumonia resolution (17), memory deficit (18), and neurocognitive problems (19).…”

Expression of the ACE2 Virus Entry Protein in the Nervus Terminalis Reveals the Potential for an Alternative Route to Brain Infection in COVID-19

“…Cell types that have been documented to be infected by SARS-CoV-2 are indicated with pink asterisks. SARS-CoV-2 localization in SUS cells according to Bryche et al (2020) ; Leist et al (2020) , Ye et al (2020) ; Zhang et al (2020) , Zheng et al (2021) ; de Melo et al (2021) , and in BG cells according to Bryche et al (2020) ; Leist et al (2020) , and Ye et al (2020) . BG cells furthermore express the protease furin ( Ueha et al, 2021 ) which may facilitate virus entry into those nervus terminalis neurons which innervate BG cells.…”

“…The nervus terminalis has direct projections into the forebrain, reaching as far caudal as the hypothalamus ( von Bartheld, 2004 ), and if the virus indeed infects these neurons, this could explain why the virus reaches the brain and cerebrospinal fluid (CSF) spaces much faster than seems possible via “neuron hopping” along olfactory projections. Most of the virus-containing axons in the olfactory nerve demonstrated by de Melo et al (2021) do not express olfactory marker protein, suggesting that they are not axons belonging to olfactory receptor neurons, and therefore may be nervus terminalis axons which also project along the olfactory nerve ( Larsell, 1950 ).…”

“…Because sustentacular cells tightly enwrap olfactory receptor neurons ( Liang, 2020 ), these ACE2-expressing support cells can easily be mistaken for olfactory receptor neurons, resulting in false positive identification. (2) The timeline of appearance of SARS-CoV-2 in the brain is inconsistent with a “neuron-hopping” mode: infection of third-order olfactory targets should occur with a significant delay after infection of the olfactory epithelium, as has been reported for other neuro-invasive viruses ( Barnett et al, 1995 ), but instead the hypothalamus and brainstem are reported to be infected as early as, or even earlier than, the olfactory bulb ( de Melo et al, 2021 ; Zheng et al, 2021 ), and SARS-CoV-2 may even skip the olfactory nerve and olfactory bulb on its way to brain infection ( Winkler et al, 2020 ; Zhou et al, 2020 ; Carossino et al, 2021 ). These findings have raised doubt about the notion that the olfactory nerve serves as a major conduit for brain infection in COVID-19 ( Butowt et al, 2021 ).…”