Direct neuronal infection of SARS-CoV-2 reveals cellular and molecular pathology of chemosensory impairment of COVID-19 patients

Abstract

Patients with recent pandemic coronavirus disease 19 (COVID-19) complain of neurological abnormalities in sensory functions such as smell and taste in the early stages of infection. Determining the cellular and molecular mechanism of sensory impairment is critical to understand the pathogenesis of clinical manifestations, as well as in setting therapeutic targets for sequelae and recurrence. The absence of studies utilizing proper models of human peripheral nerve hampers an understanding of COVID-19 pathogenesis. Here, we report that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly infects human peripheral sensory neurons, leading to molecular pathogenesis for chemosensory impairments. An in vitro system utilizing human embryonic stem cell (hESC)-derived peripheral neurons was used to model the cellular and molecular pathologies responsible for symptoms that most COVID-19 patients experience early in infection or may develop as sequelae. Peripheral neurons differentiated from hESCs expressed viral entry factor ACE2, and were directly infected with SARS-CoV-2 via ACE2. Human peripheral neurons infected with SARS-CoV-2 exhibited impaired molecular features of chemosensory function associated with abnormalities in sensory neurons of the olfactory or gustatory organs. Our results provide new insights into the pathogenesis of chemosensory dysfunction in patients with COVID-19.

COVID-19 Induced Taste Dysfunction and Recovery: Association with Smell Dysfunction and Oral Health Behaviour

“…Recent work confirms that viral particles are detectable in the taste receptors of 75% of COVID-19 positive cadavers [58]. It has also been demonstrated in vitro that direct ACE-2 mediated viral entry into olfactory and gustatory neurones [59]. Salivary glands may present a further mechanism of viral entry and dissemination [60].…”

Association between chemosensory impairment with neuropsychiatric morbidity in post-acute COVID-19 syndrome: results from a multidisciplinary cohort study

“…There is a possibility that anterograde pathogenic transmission of SARS-CoV-2 infected with the olfactory system may cause symptoms in the brain [ 31 ]. Although very small but apparently, human olfactory neurons with SARS-CoV-2 infection have been reported in autopsy [ 32 ] and in vitro [ 33 ], linking chemosensory dysfunction to brain impairment. Since reaching the nervous system, SARS-CoV-2 might induce a cascade of several different cellular and molecular processes producing neuropathological impairments with similar features of some neurodegenerative diseases [ 34 ].…”

Phenotype-driven identification of drug targets for post-COVID-19 anosmia

“…A lung transcriptome study showed that the activity of EGR1 as a transcription factor was modulated by viral proteins, with the effect of inhibiting hypoxia response 17 , a dysregulation which had been seen prior to COVID-19 18 . Secondly, expression profiling of sensory neurons after SARS-CoV-2 infection showed statistically significant increase in EGR1 expression 19 . Given that NRP1 is a secondary route for viral entry of SARS-CoV-2, and NRP1 is highly expressed in the OB, olfactory sensory neurons could be infected by this route with corresponding increased expression of EGR1 as a result.…”