Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

Brann, David H.; Tsukahara, Tatsuya; Weinreb, Caleb; Lipovsek, Marcela; Berge, Koen Van Den; Gong, Boying; Chance, Rebecca K.; Macaulay, Iain C.; Chou, Hsin Jung; Fletcher, Russell B.; Das, Diya; Street, Kelly; Bézieux, Hector Roux de; Choi, Yoon Gi; Risso, Davide; Dudoit, Sandrine; Purdom, Elizabeth; Mill, Jonathan; Hachem, Ralph Abi; Matsunami, Hiroaki; Logan, Darren W.; Goldstein, Bradley J.; Grubb, Matthew S.; Ngai, John; Datta, Sandeep Robert

doi:10.1126/sciadv.abc5801

Cited by 945 publications

(791 citation statements)

References 131 publications

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“…3D), possibly due to loss of cell markers during SARS-CoV-2 infection, as has also been observed with influenza infection [36]. Similar to what others have observed [11, 12, 37], we found low level expression of ACE2 in our primary human epithelial cells (Fig. 3A-E), likely reflecting the limited sensitivity of scRNA sequencing.…”

Section: Resultssupporting

confidence: 88%

Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium

Fiege

Thiede

Nanda

et al. 2020

Preprint

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The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-Sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of cell types are susceptible to infection, ciliated cells are a predominant cell target for SARS-CoV-2. Remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. We also found that heavily infected epithelial cells demonstrate impaired IFN signaling and express abundant IL-6, a potential mediator of COVID-19 pathogenesis.

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Section: Resultssupporting

confidence: 88%

Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium

Fiege

Thiede

Nanda

et al. 2020

Preprint

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“…The anatomy of the olfactory recess and the relationship among the nasal epithelium, OB, and CNS allows for a natural pathway for virus spread via neuronal transport. 25 Trans-synaptic transfer of virus is described in SARS-CoV 26 and Middle East respiratory syndrome coronavirus, 27 betacoronaviruses homologous to SARS-CoV-2 and responsible for previous epidemics. Preclinical experiments in transgenic mice demonstrated that the intranasal introduction of these viruses resulted in CNS inoculation, with neuronal loss in areas of viral expression.…”

Section: Discussionmentioning

confidence: 99%

“…Findings remain significant even with the exclusion of the COVID-19 high outlier depicted at a mean normalized OB T2 FLAIR signal intensity of 3.1. in sustentacular and olfactory stem cells and may serve as a putative target for SARS-CoV-2 infection of olfactory epithelium. 25 Alternatively, viral binding to angiotensin-converting enzyme 2 receptors expressed in CNS capillary endothelium might result in endothelial damage, which enables spike protein binding to neuronal angiotensin-converting enzyme 2 receptors and subsequent CNS infection. 28 Another possibility is that hematogenous spread may occur via the blood supply shared by olfactory sensory neurons and the OB.…”

Section: Discussionmentioning

confidence: 99%

Olfactory Bulb Signal Abnormality in Patients with COVID-19 Who Present with Neurologic Symptoms

Strauß

Lantos

Heier

et al. 2020

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE: Unique among the acute neurologic manifestations of Severe Acute Respiratory Syndrome coronavirus 2, the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, is chemosensory dysfunction (anosmia or dysgeusia), which can be seen in patients who are otherwise oligosymptomatic or even asymptomatic. The purpose of this study was to determine if there is imaging evidence of olfactory apparatus pathology in patients with COVID-19 and neurologic symptoms. MATERIALS AND METHODS: A retrospective case-control study compared the olfactory bulb and olfactory tract signal intensity on thin-section T2WI and postcontrast 3D T2 FLAIR images in patients with COVID-19 and neurologic symptoms, and age-matched controls imaged for olfactory dysfunction. RESULTS: There was a significant difference in normalized olfactory bulb T2 FLAIR signal intensity between the patients with COVID-19 and the controls with anosmia (P ¼ .003). Four of 12 patients with COVID-19 demonstrated intraneural T2 signal hyperintensity on postcontrast 3D T2 FLAIR compared with none of the 12 patients among the controls with anosmia (P ¼ .028). CONCLUSIONS: Olfactory bulb 3D T2 FLAIR signal intensity was greater in the patients with COVID-19 and neurologic symptoms compared with an age-matched control group with olfactory dysfunction, and this was qualitatively apparent in 4 of 12 patients with COVID-19. Analysis of these preliminary finding suggests that olfactory apparatus vulnerability to COVID-19 might be supported on conventional neuroimaging and may serve as a noninvasive biomarker of infection. ABBREVIATIONS: COVID-19 ¼ coronavirus disease 2019; OB ¼ olfactory bulb; SARS-CoV-2 ¼ Severe Acute Respiratory Syndrome coronavirus 2 S evere Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, may produce a broad range of acute neurologic symptoms that involve both the CNS and the peripheral nervous system, including stroke, 1 meningitis, encephalitis, Guillain-Barré syndrome, and acute necrotizing hemorrhagic encephalopathy. 2 Unique among these acute neurologic manifestations is chemosensory dysfunction (anosmia or dysgeusia), which can be seen in patients who are otherwise oligosymptomatic or even asymptomatic. A single-institution report from the United States that involved 1480 patients with COVID-19

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“…As far as SARS-CoV and MERS-CoV are concerned, experimental studies of animal models showed that SARS-CoV and MERS-CoV, when given through the nose, possibly invade the cerebrum via the olfactory nerves, spreading to some regions of the brain including thalamus and brainstem (8,20,34). Notably, it has been suggested that ACE2 olfactory (epithelial) support cells and stem cells produce ACE2 genes, as do cells located in the epithelium of the nasal respiratory tract in patients afflicted with COVID-19, which may show some parallels with attentiondeficit/hyperactivity disorder (39)(40)(41). So far, in the light of the evidence provided enough, it is conceivable that SARS-CoV-2 is neuroinvasive, and it uses ACE2 as receptors to penetrate the cell (13).…”

Section: Neuroinvasion Of Sars-cov-2 and Samhd1mentioning

confidence: 99%

SAMHD1 as the Potential Link Between SARS-CoV-2 Infection and Neurological Complications

Khan

Sergi

2020

Front. Neurol.

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The recent pandemic of coronavirus infectious illness 2019 (COVID19) triggered by SARS-CoV-2 has rapidly spread around the globe, generating in severe events an acute, highly lethal pneumonia and death. In the past two hitherto similar CoVs, the severe acute respiratory syndrome CoV (SARS-CoV-1) and Middle East respiratory syndrome CoV (MERS-CoV) also gained universal attention as they produced clinical symptoms similar to those of SARS-CoV-2 utilizing angiotensin-converting enzyme 2 (ACE2) receptor and dipeptidyl peptidase 4 (DPP4) to go into the cells. COVID-19 may also present with overtly neurological symptoms. The proper understanding of the expression and dissemination of ACE2 in central and peripheral nerve systems is crucial to understand better the neurological morbidity caused by COVID-19. Using the STRING bioinformatic tool and references through text mining tools associated to Coronaviruses, we identified SAMHD1 as the probable link to neurological symptoms. Paralleled to the response to influenza A virus and, specifically, respiratory syncytial virus, SARS-CoV-2 evokes a response that needs robust induction of a subclass of cytokines, including the Type I and, obviously, Type III interferons as well as a few chemokines. We correlate ACE2 to the pathogenesis and neurologic complications of COVID-19 and found that SAMHD1 links to NF-κB pathway. No correlation was found with other molecules associated with Coronavirus infection, including ADAR, BST2, IRF3, IFITM3, ISG15, MX1, MX2, RNASEL, RSAD2, and VPRBP. We suggest that SAMHD1 is the molecule that may be behind the mechanisms of the neurological complications associated with COVID-19.

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Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

Cited by 945 publications

References 131 publications

Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium

Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium

Olfactory Bulb Signal Abnormality in Patients with COVID-19 Who Present with Neurologic Symptoms

SAMHD1 as the Potential Link Between SARS-CoV-2 Infection and Neurological Complications

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