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1.
Lancet Neurol ; 20(9): 753-761, 2021 09.
Article in English | MEDLINE | ID: covidwho-1599333

ABSTRACT

BACKGROUND: The mechanisms by which any upper respiratory virus, including SARS-CoV-2, impairs chemosensory function are not known. COVID-19 is frequently associated with olfactory dysfunction after viral infection, which provides a research opportunity to evaluate the natural course of this neurological finding. Clinical trials and prospective and histological studies of new-onset post-viral olfactory dysfunction have been limited by small sample sizes and a paucity of advanced neuroimaging data and neuropathological samples. Although data from neuropathological specimens are now available, neuroimaging of the olfactory system during the acute phase of infection is still rare due to infection control concerns and critical illness and represents a substantial gap in knowledge. RECENT DEVELOPMENTS: The active replication of SARS-CoV-2 within the brain parenchyma (ie, in neurons and glia) has not been proven. Nevertheless, post-viral olfactory dysfunction can be viewed as a focal neurological deficit in patients with COVID-19. Evidence is also sparse for a direct causal relation between SARS-CoV-2 infection and abnormal brain findings at autopsy, and for trans-synaptic spread of the virus from the olfactory epithelium to the olfactory bulb. Taken together, clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in either the olfactory epithelium, the olfactory bulb, or both. This inflammation leads to persistent olfactory deficits in a subset of people who have recovered from COVID-19. Neuroimaging has revealed localised inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen. WHERE NEXT?: The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease.


Subject(s)
COVID-19/complications , COVID-19/diagnostic imaging , Olfaction Disorders/diagnostic imaging , Olfaction Disorders/etiology , Olfactory Mucosa/diagnostic imaging , Brain/diagnostic imaging , Brain/physiopathology , Brain/virology , COVID-19/physiopathology , Humans , Neurodegenerative Diseases/diagnostic imaging , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/physiopathology , Olfaction Disorders/physiopathology , Olfaction Disorders/virology , Olfactory Mucosa/physiopathology , Olfactory Mucosa/virology , Prospective Studies , Smell/physiology
2.
Int J Med Sci ; 18(10): 2102-2108, 2021.
Article in English | MEDLINE | ID: covidwho-1389721

ABSTRACT

Introduction: SARS-CoV-2 is a respiratory virus supposed to enter the organism through aerosol or fomite transmission to the nose, eyes and oropharynx. It is responsible for various clinical symptoms, including hyposmia and other neurological ones. Current literature suggests the olfactory mucosa as a port of entry to the CNS, but how the virus reaches the olfactory groove is still unknown. Because the first neurological symptoms of invasion (hyposmia) do not correspond to first signs of infection, the hypothesis of direct contact through airborne droplets during primary infection and therefore during inspiration is not plausible. The aim of this study is to evaluate if a secondary spread to the olfactory groove in a retrograde manner during expiration could be more probable. Methods: Four three-dimensional virtual models were obtained from actual CT scans and used to simulate expiratory droplets. The volume mesh consists of 25 million of cells, the simulated condition is a steady expiration, driving a flow rate of 270 ml/s, for a duration of 0.6 seconds. The droplet diameter is of 5 µm. Results: The analysis of the simulations shows the virus to have a high probability to be deployed in the rhinopharynx, on the tail of medium and upper turbinates. The possibility for droplets to access the olfactory mucosa during the expiratory phase is lower than other nasal areas, but consistent. Discussion: The data obtained from these simulations demonstrates the virus can be deployed in the olfactory groove during expiration. Even if the total amount in a single act is scarce, it must be considered it is repeated tens of thousands of times a day, and the source of contamination continuously acts on a timescale of several days. The present results also imply CNS penetration of SARS-CoV-2 through olfactory mucosa might be considered a complication and, consequently, prevention strategies should be considered in diseased patients.


Subject(s)
Olfactory Mucosa/virology , SARS-CoV-2/pathogenicity , Biomechanical Phenomena , Computer Simulation , Host-Pathogen Interactions/physiology , Humans , Hydrodynamics , Olfactory Mucosa/diagnostic imaging
3.
Neuropharmacology ; 198: 108766, 2021 10 15.
Article in English | MEDLINE | ID: covidwho-1376075

ABSTRACT

The coronavirus disease 2019 (Covid-19) pandemic intensified the already catastrophic drug overdose and substance use disorder (SUD) epidemic, signaling a syndemic as social isolation, economic and mental health distress, and disrupted treatment services disproportionally impacted this vulnerable population. Along with these social and societal factors, biological factors triggered by intense stress intertwined with incumbent overactivity of the immune system and the resulting inflammatory outcomes may impact the functional status of the central nervous system (CNS). We review the literature concerning SARS-CoV2 infiltration and infection in the CNS and the prospects of synergy between stress, inflammation, and kynurenine pathway function during illness and recovery from Covid-19. Taken together, inflammation and neuroimmune signaling, a consequence of Covid-19 infection, may dysregulate critical pathways and underlie maladaptive changes in the CNS, to exacerbate the development of neuropsychiatric symptoms and in the vulnerability to develop SUD. This article is part of the special Issue on 'Vulnerabilities to Substance Abuse'.


Subject(s)
COVID-19/epidemiology , Drug Misuse/statistics & numerical data , SARS-CoV-2 , Substance-Related Disorders/epidemiology , Adaptation, Psychological , Angiotensin-Converting Enzyme 2/physiology , Animals , Axons/virology , COVID-19/immunology , COVID-19/physiopathology , COVID-19/psychology , Comorbidity , Disease Susceptibility , Endothelial Cells/virology , Humans , Immunity, Innate , Inflammation/etiology , Kynurenine/metabolism , Neurons/virology , Neurotransmitter Agents/metabolism , Olfactory Mucosa/virology , Pandemics , SARS-CoV-2/physiology , Social Isolation , Stress, Psychological , Substance-Related Disorders/etiology , Substance-Related Disorders/physiopathology , Tryptophan/metabolism , Viral Tropism
4.
Viruses ; 13(8)2021 08 20.
Article in English | MEDLINE | ID: covidwho-1367922

ABSTRACT

Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019, suffer from respiratory and non-respiratory symptoms. Among these symptoms, the loss of smell has attracted considerable attention. The objectives of this study were to determine which cells are infected, what happens in the olfactory system after viral infection, and how these pathologic changes contribute to olfactory loss. For this purpose, Syrian golden hamsters were used. First, we verified the olfactory structures in the nasal cavity of Syrian golden hamsters, namely the main olfactory epithelium, the vomeronasal organ, and their cellular components. Second, we found angiotensin-converting enzyme 2 expression, a receptor protein of SARS-CoV-2, in both structures and infections of supporting, microvillar, and solitary chemosensory cells. Third, we observed pathological changes in the infected epithelium, including reduced thickness of the mucus layer, detached epithelia, indistinct layers of epithelia, infiltration of inflammatory cells, and apoptotic cells in the overall layers. We concluded that a structurally and functionally altered microenvironment influences olfactory function. We observed the regeneration of the damaged epithelium, and found multilayers of basal cells, indicating that they were activated and proliferating to reconstitute the injured epithelium.


Subject(s)
COVID-19/virology , Chemoreceptor Cells/virology , Olfactory Mucosa/virology , SARS-CoV-2 , Vomeronasal Organ/virology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/pathology , Chemoreceptor Cells/pathology , Male , Mesocricetus , Nasal Cavity/pathology , Nasal Cavity/virology , Olfactory Mucosa/metabolism , Olfactory Mucosa/pathology , Olfactory Receptor Neurons/metabolism , Olfactory Receptor Neurons/pathology , Olfactory Receptor Neurons/virology , Receptors, Coronavirus/metabolism , Regeneration , SARS-CoV-2/isolation & purification , Vomeronasal Organ/metabolism , Vomeronasal Organ/pathology
5.
J Med Virol ; 93(7): 4247-4257, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1269115

ABSTRACT

To provide instructive clues for clinical practice and further research of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we analyzed the existing literature on viral neuroinvasion of SARS-CoV-2 in coronavirus disease 2019 (COVID-19) patients. To date, SARS-CoV-2 has been detected in the cerebrospinal fluid (CSF) or brain parenchyma in quite a few patients, which provide undeniable evidence for the neuroinvasive potential of this novel coronavirus. In contrast with the cerebrum and cerebellum, the detection rate of SARS-CoV-2 was higher in the olfactory system and the brainstem, both of which also showed severe microgliosis and lymphocytic infiltrations. As compared with the number of patients who underwent viral testing in the central nervous system (CNS), the number of patients showing positive results seems very small. However, it seems too early to conclude that the neuroinvasion of SARS-CoV-2 is rare in COVID-19 patients because the detection methods or sampling procedures in some studies may not be suitable or sufficient to reveal the CNS infection induced by neurotropic viruses. Moreover, the primary symptoms and/or causes of death were distinctly different among examined patients, which probably caused more conspicuous pathological changes than those due to the direct infection that usually localized to specific brain areas. Unfortunately, most autopsy studies did not provide sufficient details about neurological symptoms or suspected diagnoses of the examined patients, and the documentation of neuropathological changes was often incomplete. Given the complex pathophysiology of COVID-19 and the characteristics of neurotropic viruses, it is understandable that any study of the CNS infection may inevitably have limitations.


Subject(s)
Brain/pathology , COVID-19/pathology , Cerebrospinal Fluid/virology , Olfactory Bulb/virology , Antibodies, Viral/blood , Antibodies, Viral/cerebrospinal fluid , Brain/virology , Humans , Nervous System Diseases/virology , Olfactory Mucosa/virology , SARS-CoV-2/isolation & purification
6.
Sci Transl Med ; 13(596)2021 06 02.
Article in English | MEDLINE | ID: covidwho-1214961

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.


Subject(s)
Anosmia/virology , Brain/virology , COVID-19 , Olfactory Mucosa/pathology , Animals , COVID-19/pathology , Cricetinae , Humans , Inflammation , Olfactory Mucosa/virology , RNA, Viral , SARS-CoV-2
7.
Int J Mol Sci ; 21(18)2020 Sep 15.
Article in English | MEDLINE | ID: covidwho-1207809

ABSTRACT

The recent coronavirus disease (COVID-19) is still spreading worldwide. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for COVID-19, binds to its receptor angiotensin-converting enzyme 2 (ACE2), and replicates within the cells of the nasal cavity, then spreads along the airway tracts, causing mild clinical manifestations, and, in a majority of patients, a persisting loss of smell. In some individuals, SARS-CoV-2 reaches and infects several organs, including the lung, leading to severe pulmonary disease. SARS-CoV-2 induces neurological symptoms, likely contributing to morbidity and mortality through unknown mechanisms. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with pleiotropic properties and functions in many tissues, including the nervous system. S1P regulates neurogenesis and inflammation and it is implicated in multiple sclerosis (MS). Notably, Fingolimod (FTY720), a modulator of S1P receptors, has been approved for the treatment of MS and is being tested for COVID-19. Here, we discuss the putative role of S1P on viral infection and in the modulation of inflammation and survival in the stem cell niche of the olfactory epithelium. This could help to design therapeutic strategies based on S1P-mediated signaling to limit or overcome the host-virus interaction, virus propagation and the pathogenesis and complications involving the nervous system.


Subject(s)
Coronavirus Infections/pathology , Lysophospholipids/metabolism , Nervous System/metabolism , Pneumonia, Viral/pathology , Sphingosine-1-Phosphate Receptors/metabolism , Sphingosine/analogs & derivatives , Angiotensin-Converting Enzyme 2 , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/virology , Cytokines/metabolism , Humans , Olfactory Mucosa/metabolism , Olfactory Mucosa/virology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , SARS-CoV-2 , Severity of Illness Index , Signal Transduction , Sphingosine/metabolism
8.
Int Forum Allergy Rhinol ; 11(7): 1041-1046, 2021 07.
Article in English | MEDLINE | ID: covidwho-1136915

ABSTRACT

The frequent association between coronavirus disease 2019 (COVID-19) and olfactory dysfunction is creating an unprecedented demand for a treatment of the olfactory loss. Systemic corticosteroids have been considered as a therapeutic option. However, based on current literature, we call for caution using these treatments in early COVID-19-related olfactory dysfunction because: (1) evidence supporting their usefulness is weak; (2) the rate of spontaneous recovery of COVID-19-related olfactory dysfunction is high; and (3) corticosteroids have well-known potential adverse effects. We encourage randomized placebo-controlled trials investigating the efficacy of systemic steroids in this indication and strongly emphasize to initially consider smell training, which is supported by a robust evidence base and has no known side effects.


Subject(s)
Adrenal Cortex Hormones/pharmacology , COVID-19 , Medication Therapy Management/statistics & numerical data , Olfaction Disorders , COVID-19/complications , COVID-19/physiopathology , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/prevention & control , Global Health , Humans , Medication Therapy Management/standards , Needs Assessment , Olfaction Disorders/drug therapy , Olfaction Disorders/epidemiology , Olfaction Disorders/etiology , Olfactory Mucosa/drug effects , Olfactory Mucosa/virology , Remission, Spontaneous , Research Design , SARS-CoV-2/pathogenicity
9.
PLoS One ; 16(2): e0244127, 2021.
Article in English | MEDLINE | ID: covidwho-1067399

ABSTRACT

INTRODUCTION: Olfactory dysfunction (OD) affects a majority of COVID-19 patients, is atypical in duration and recovery, and is associated with focal opacification and inflammation of the olfactory epithelium. Given recent increased emphasis on airborne transmission of SARS-CoV-2, the purpose of the present study was to experimentally characterize aerosol dispersion within olfactory epithelium (OE) and respiratory epithelium (RE) in human subjects, to determine if small (sub 5µm) airborne aerosols selectively deposit in the OE. METHODS: Healthy adult volunteers inhaled fluorescein-labeled nebulized 0.5-5µm airborne aerosol or atomized larger aerosolized droplets (30-100µm). Particulate deposition in the OE and RE was assessed by blue-light filter modified rigid endoscopic evaluation with subsequent image randomization, processing and quantification by a blinded reviewer. RESULTS: 0.5-5µm airborne aerosol deposition, as assessed by fluorescence gray value, was significantly higher in the OE than the RE bilaterally, with minimal to no deposition observed in the RE (maximum fluorescence: OE 19.5(IQR 22.5), RE 1(IQR 3.2), p<0.001; average fluorescence: OE 2.3(IQR 4.5), RE 0.1(IQR 0.2), p<0.01). Conversely, larger 30-100µm aerosolized droplet deposition was significantly greater in the RE than the OE (maximum fluorescence: OE 13(IQR 14.3), RE 38(IQR 45.5), p<0.01; average fluorescence: OE 1.9(IQR 2.1), RE 5.9(IQR 5.9), p<0.01). CONCLUSIONS: Our data experimentally confirm that despite bypassing the majority of the upper airway, small-sized (0.5-5µm) airborne aerosols differentially deposit in significant concentrations within the olfactory epithelium. This provides a compelling aerodynamic mechanism to explain atypical OD in COVID-19.


Subject(s)
Aerosols/analysis , Anosmia/etiology , COVID-19/complications , Olfactory Mucosa/physiopathology , Adult , Aerosols/administration & dosage , Anosmia/physiopathology , Anosmia/virology , COVID-19/physiopathology , COVID-19/virology , Host-Pathogen Interactions , Humans , Olfactory Mucosa/virology , SARS-CoV-2/physiology , Smell
10.
Nat Neurosci ; 24(2): 168-175, 2021 02.
Article in English | MEDLINE | ID: covidwho-1060446

ABSTRACT

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.


Subject(s)
Brain/virology , COVID-19/virology , Olfactory Mucosa/virology , SARS-CoV-2/pathogenicity , Central Nervous System , Humans , RNA, Viral/genetics , Smell/physiology , Virus Internalization
11.
Cells Tissues Organs ; 209(4-6): 155-164, 2020.
Article in English | MEDLINE | ID: covidwho-1042717

ABSTRACT

Usually, pandemic COVID-19 disease, caused by SARS-CoV2, presents with mild respiratory symptoms such as fever, cough, but frequently also with anosmia and neurological symptoms. Virus-cell fusion is mediated by angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) with their organ expression pattern determining viral tropism. Clinical presentation suggests rapid viral dissemination to the central nervous system leading frequently to severe symptoms including viral meningitis. Here, we provide a comprehensive expression landscape of ACE2 and TMPRSS2 proteins across human postmortem nasal and olfactory tissue. Sagittal sections through the human nose complemented with immunolabelling of respective cell types represent different anatomically defined regions including olfactory epithelium, respiratory epithelium of the nasal conchae and the paranasal sinuses along with the hardly accessible human olfactory bulb. ACE2 can be detected in the olfactory epithelium as well as in the respiratory epithelium of the nasal septum, the nasal conchae, and the paranasal sinuses. ACE2 is located in the sustentacular cells and in the glandular cells in the olfactory epithelium as well as in the basal cells, glandular cells, and epithelial cells of the respiratory epithelium. Intriguingly, ACE2 is not expressed in mature or immature olfactory receptor neurons and basal cells in the olfactory epithelium. Similarly, ACE2 is not localized in the olfactory receptor neurons albeit the olfactory bulb is positive. Vice versa, TMPRSS2 can also be detected in the sustentacular cells and the glandular cells of the olfactory epithelium. Our findings provide the basic anatomical evidence for the expression of ACE2 and TMPRSS2 in the human nose, olfactory epithelium, and olfactory bulb. Thus, they are substantial for future studies that aim to elucidate the symptom of SARS-CoV2 induced anosmia via the olfactory pathway.


Subject(s)
Angiotensin-Converting Enzyme 2/analysis , COVID-19/pathology , Nasal Mucosa/pathology , Olfactory Bulb/pathology , SARS-CoV-2/isolation & purification , Serine Endopeptidases/analysis , COVID-19/diagnosis , Humans , Nasal Mucosa/virology , Nose/pathology , Nose/virology , Olfactory Bulb/virology , Olfactory Mucosa/pathology , Olfactory Mucosa/virology
12.
Nat Neurosci ; 24(2): 168-175, 2021 02.
Article in English | MEDLINE | ID: covidwho-952133

ABSTRACT

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.


Subject(s)
Brain/virology , COVID-19/virology , Olfactory Mucosa/virology , SARS-CoV-2/pathogenicity , Central Nervous System , Humans , RNA, Viral/genetics , Smell/physiology , Virus Internalization
13.
J Laryngol Otol ; 134(12): 1123-1127, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-943804

ABSTRACT

BACKGROUND: Olfactory dysfunction represents one of the most frequent symptoms of coronavirus disease 2019, affecting about 70 per cent of patients. However, the pathogenesis of the olfactory dysfunction in coronavirus disease 2019 has not yet been elucidated. CASE REPORT: This report presents the radiological and histopathological findings of a patient who presented with anosmia persisting for more than three months after infection with severe acute respiratory syndrome coronavirus-2. CONCLUSION: The biopsy demonstrated significant disruption of the olfactory epithelium. This shifts the focus away from invasion of the olfactory bulb and encourages further studies of treatments targeted at the surface epithelium.


Subject(s)
Anosmia/etiology , COVID-19/complications , Olfaction Disorders/physiopathology , Olfactory Mucosa/pathology , Anosmia/diagnosis , Anosmia/drug therapy , Anosmia/virology , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , Cortisone/administration & dosage , Cortisone/therapeutic use , Female , Humans , Magnetic Resonance Imaging/methods , Middle Aged , Olfactory Bulb/diagnostic imaging , Olfactory Mucosa/virology , SARS-CoV-2/genetics , Treatment Outcome
14.
Med Hypotheses ; 146: 110406, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-939150

ABSTRACT

Three mechanisms have been proposed to account for COVID-19 associated olfactory dysfunction; obstruction of the olfactory cleft; epithelial injury and infection of the sustentacular supporting cells, which are known to express ACE2, or injury to the olfactory bulb due to axonal transport through olfactory sensory neurones. The absence of ACE2 expression by olfactory sensory neurones has led to the neurotropic potential of COVID-19 to be discounted. While an accumulating body of evidence supports olfactory epithelial injury as an important mechanism, this does not account for all the features of olfactory dysfunction seen in COVID-19; for example the duration of loss in some patients, evidence of changes within the olfactory bulb on MRI imaging, identification of viral particles within the olfactory bulb in post-mortem specimens and the inverse association between severity of COVID-19 and the prevalence of olfactory loss. The recent identification of a second route of viral entry mediated by NRP1 addresses many of these inconsistencies. Expression by the olfactory sensory neurones and their progenitor cells may facilitate direct injury and axonal transport to the olfactory bulb as well as a mechanism for delayed or absent recovery. Expression by regulatory T cells may play a central role in the cytokine storm. Variability in expression by age, race or gender may explain differing morbidity of infection and inverse association between anosmia and severity; in the case of higher expression there may be a higher risk of olfactory function but greater activation of regulatory T cells that may suppress the cytokine storm.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , COVID-19/complications , COVID-19/physiopathology , Models, Biological , Neuropilin-1/physiology , Olfaction Disorders/etiology , Olfaction Disorders/physiopathology , SARS-CoV-2 , Anosmia/etiology , Anosmia/physiopathology , COVID-19/virology , Humans , Magnetic Resonance Imaging , Olfaction Disorders/virology , Olfactory Bulb/diagnostic imaging , Olfactory Bulb/physiopathology , Olfactory Mucosa/injuries , Olfactory Mucosa/physiopathology , Olfactory Mucosa/virology , Olfactory Receptor Neurons/physiology , SARS-CoV-2/pathogenicity , Severity of Illness Index , Smell/physiology , T-Lymphocytes, Regulatory/immunology , Virus Internalization
15.
Science ; 370(6518): 856-860, 2020 11 13.
Article in English | MEDLINE | ID: covidwho-883299

ABSTRACT

The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. In this study, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. A SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of olfactory epithelium obtained from human COVID-19 autopsies revealed that SARS-CoV-2 infected NRP1-positive cells facing the nasal cavity. Our data provide insight into SARS-CoV-2 cell infectivity and define a potential target for antiviral intervention.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Neuropilin-1/metabolism , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Monoclonal/immunology , Betacoronavirus/genetics , COVID-19 , Caco-2 Cells , Female , HEK293 Cells , Host Microbial Interactions , Humans , Lung/metabolism , Male , Metal Nanoparticles , Mice , Mice, Inbred C57BL , Mutation , Neuropilin-1/chemistry , Neuropilin-1/genetics , Neuropilin-1/immunology , Neuropilin-2/metabolism , Olfactory Mucosa/metabolism , Olfactory Mucosa/virology , Pandemics , Peptide Fragments/metabolism , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Protein Domains , Respiratory Mucosa/metabolism , SARS-CoV-2 , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/chemistry
16.
Brain Behav Immun ; 89: 579-586, 2020 10.
Article in English | MEDLINE | ID: covidwho-656807

ABSTRACT

Anosmia is one of the most prevalent symptoms of SARS-CoV-2 infection during the COVID-19 pandemic. However, the cellular mechanism behind the sudden loss of smell has not yet been investigated. The initial step of odour detection takes place in the pseudostratified olfactory epithelium (OE) mainly composed of olfactory sensory neurons surrounded by supporting cells known as sustentacular cells. The olfactory neurons project their axons to the olfactory bulb in the central nervous system offering a potential pathway for pathogens to enter the central nervous system by bypassing the blood brain barrier. In the present study, we explored the impact of SARS-CoV-2 infection on the olfactory system in golden Syrian hamsters. We observed massive damage of the OE as early as 2 days post nasal instillation of SARS-CoV-2, resulting in a major loss of cilia necessary for odour detection. These damages were associated with infection of a large proportion of sustentacular cells but not of olfactory neurons, and we did not detect any presence of the virus in the olfactory bulbs. We observed massive infiltration of immune cells in the OE and lamina propria of infected animals, which may contribute to the desquamation of the OE. The OE was partially restored 14 days post infection. Anosmia observed in COVID-19 patient is therefore likely to be linked to a massive and fast desquamation of the OE following sustentacular cells infection with SARS-CoV-2 and subsequent recruitment of immune cells in the OE and lamina propria.


Subject(s)
Coronavirus Infections/pathology , Olfactory Bulb/pathology , Olfactory Mucosa/pathology , Pneumonia, Viral/pathology , Animals , Betacoronavirus , COVID-19 , Cilia/pathology , Coronavirus Infections/physiopathology , Mesocricetus , Olfaction Disorders/pathology , Olfaction Disorders/physiopathology , Olfactory Bulb/virology , Olfactory Mucosa/virology , Olfactory Receptor Neurons/pathology , Olfactory Receptor Neurons/virology , Pandemics , Pneumonia, Viral/physiopathology , SARS-CoV-2
17.
Neuron ; 107(2): 219-233, 2020 07 22.
Article in English | MEDLINE | ID: covidwho-623119

ABSTRACT

The main neurological manifestation of COVID-19 is loss of smell or taste. The high incidence of smell loss without significant rhinorrhea or nasal congestion suggests that SARS-CoV-2 targets the chemical senses through mechanisms distinct from those used by endemic coronaviruses or other common cold-causing agents. Here we review recently developed hypotheses about how SARS-CoV-2 might alter the cells and circuits involved in chemosensory processing and thereby change perception. Given our limited understanding of SARS-CoV-2 pathogenesis, we propose future experiments to elucidate disease mechanisms and highlight the relevance of this ongoing work to understanding how the virus might alter brain function more broadly.


Subject(s)
Betacoronavirus , Coronavirus Infections/physiopathology , Olfaction Disorders/physiopathology , Pneumonia, Viral/physiopathology , Smell/physiology , Taste Disorders/physiopathology , Taste/physiology , Animals , COVID-19 , Coronavirus Infections/epidemiology , Humans , Olfaction Disorders/epidemiology , Olfaction Disorders/virology , Olfactory Bulb/physiopathology , Olfactory Bulb/virology , Olfactory Mucosa/physiopathology , Olfactory Mucosa/virology , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Taste Disorders/epidemiology , Taste Disorders/virology
18.
Asian Pac J Allergy Immunol ; 38(2): 69-77, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-610528

ABSTRACT

During the initial pandemic wave of COVID-19, apart from common presenting symptoms (cough, fever, and fatigue), many countries have reported a sudden increase in the number of smell and taste dysfunction patients. Smell dysfunction has been reported in other viral infections (parainfluenza, rhinovirus, SARS, and others), but the incidence is much lower than SARS-CoV-2 infection. The pathophysiology of post-infectious olfactory loss was hypothesized that viruses may produce an inflammatory reaction of the nasal mucosa or damage the olfactory neuroepithelium directly. However, loss of smell could be presented in COVID-19 patients without other rhinologic symptoms or significant nasal inflammation. This review aims to provide a brief overview of recent evidence for epidemiology, pathological mechanisms for the smell, and taste dysfunction in SARS-CoV-2 infected patients. Furthermore, prognosis and treatments are reviewed with scanty evidence. We also discuss the possibility of using "smell and taste loss" as a screening tool for COVID-19 and treatment options in the post-SARS-CoV-2 infectious olfactory loss.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Olfaction Disorders/epidemiology , Olfaction Disorders/physiopathology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , Adrenal Cortex Hormones/therapeutic use , Antiviral Agents/therapeutic use , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Humans , Incidence , Olfaction Disorders/diagnosis , Olfaction Disorders/drug therapy , Olfactory Mucosa/drug effects , Olfactory Mucosa/physiopathology , Olfactory Mucosa/virology , Olfactory Perception/drug effects , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Practice Guidelines as Topic , Prognosis , Quinoxalines/therapeutic use , Remission, Spontaneous , SARS-CoV-2 , Taste Perception/drug effects , Vitamin A/therapeutic use
19.
ACS Chem Neurosci ; 11(9): 1206-1209, 2020 05 06.
Article in English | MEDLINE | ID: covidwho-101631

ABSTRACT

The novel coronavirus SARS-CoV-2, which was identified after a recent outbreak in Wuhan, China, in December 2019, has kept the whole world in tenterhooks due to its severe life-threatening nature of the infection. The virus is unlike its previous counterparts, SARS-CoV and MERS-CoV, or anything the world has encountered before both in terms of virulence and severity of the infection. If scientific reports relevant to the SARS-CoV-2 virus are noted, it can be seen that the virus owes much of its killer properties to its unique structure that has a stronger binding affinity with the human angiotensin-converting enzyme 2 (hACE2) protein, which the viruses utilize as an entry point to gain accesses to its hosts. Recent reports suggest that it is not just the lung that the virus may be targeting; the human brain may soon emerge as the new abode of the virus. Already instances of patients with COVID-19 have been reported with mild (anosmia and ageusia) to severe (encephalopathy) neurological manifestations, and if that is so, then it gives us more reasons to be frightened of this killer virus. Keeping in mind that the situation does not worsen from here, immediate awareness and more thorough research regarding the neuroinvasive nature of the virus is the immediate need of the hour. Scientists globally also need to up their game to design more specific therapeutic strategies with the available information to counteract the pandemic. In this Viewpoint, we provide a brief outline of the currently known neurological manifestations of COVID-19 and discuss some probable ways to design therapeutic strategies to overcome the present global crisis.


Subject(s)
Betacoronavirus/pathogenicity , Brain/virology , Coronavirus Infections/physiopathology , Pneumonia, Viral/physiopathology , Aged , Ageusia/virology , Angiotensin-Converting Enzyme 2 , Autopsy , BCG Vaccine/administration & dosage , BCG Vaccine/immunology , Betacoronavirus/chemistry , Betacoronavirus/metabolism , Brain/pathology , Brain/physiopathology , Brain Diseases/immunology , Brain Diseases/pathology , Brain Diseases/virology , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/transmission , Coronavirus Infections/virology , Cytokines/immunology , Humans , Inflammation/immunology , Inflammation/pathology , Inflammation/virology , MicroRNAs/genetics , Olfaction Disorders/virology , Olfactory Mucosa/pathology , Olfactory Mucosa/physiopathology , Olfactory Mucosa/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , RNA Interference , Receptors, Nicotinic/metabolism , SARS-CoV-2 , Serine Endopeptidases/metabolism , Smoking/metabolism , Smoking/pathology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
20.
ACS Chem Neurosci ; 11(9): 1200-1203, 2020 05 06.
Article in English | MEDLINE | ID: covidwho-47704

ABSTRACT

The novel SARS-CoV-2 virus has very high infectivity, which allows it to spread rapidly around the world. Attempts at slowing the pandemic at this stage depend on the number and quality of diagnostic tests performed. We propose that the olfactory epithelium from the nasal cavity may be a more appropriate tissue for detection of SARS-CoV-2 virus at the earliest stages, prior to onset of symptoms or even in asymptomatic people, as compared to commonly used sputum or nasopharyngeal swabs. Here we emphasize that the nasal cavity olfactory epithelium is the likely site of enhanced binding of SARS-CoV-2. Multiple non-neuronal cell types present in the olfactory epithelium express two host receptors, ACE2 and TMPRSS2 proteases, that facilitate SARS-CoV-2 binding, replication, and accumulation. This may be the underlying mechanism for the recently reported cases of smell dysfunction in patients with COVID-19. Moreover, the possibility of subsequent brain infection should be considered which begins in olfactory neurons. In addition, we discuss the possibility that olfactory receptor neurons may initiate rapid immune responses at early stages of the disease. We emphasize the need to undertake research focused on additional aspects of SARS-CoV-2 actions in the nervous system, especially in the olfactory pathway.


Subject(s)
Betacoronavirus/isolation & purification , Brain/virology , Coronavirus Infections/diagnosis , Early Diagnosis , Mass Screening/methods , Olfactory Mucosa/virology , Pneumonia, Viral/diagnosis , Smell , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/growth & development , Betacoronavirus/immunology , Brain/immunology , Brain/physiopathology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Coronavirus Infections/transmission , Humans , Immunity, Innate , Mass Screening/standards , Mice , Olfactory Mucosa/cytology , Olfactory Mucosa/immunology , Olfactory Mucosa/metabolism , Olfactory Receptor Neurons/immunology , Olfactory Receptor Neurons/metabolism , Olfactory Receptor Neurons/virology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/transmission , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology , SARS-CoV-2 , Serine Endopeptidases/metabolism , Virus Replication
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