Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb

Khan, Mona; Yoo, Sung Jin; Clijsters, Marnick; Backaert, Wout; Vanstapel, Arno; Speleman, Kato; Lietaer, Charlotte; Choi, Sungjun; Hether, Tyler; Marcelis, Lukas; Nam, Andrew; Pan, Liuliu; Reeves, Jason; Bulck, Pauline Van; Zhou, Hai; Bourgeois, Marc; Debaveye, Yves; Munter, Paul De; Gunst, Jan; Jorissen, Mark; Lagrou, Katrien; Lorent, Natalie; Neyrinck, Arne; Peetermans, Marijke; Thal, Dietmar Rudolf; Vandenbriele, Christophe; Wauters, Joost; Mombaerts, Peter; Gerven, Laura Van

doi:10.1016/j.cell.2021.10.027

Cited by 271 publications

(327 citation statements)

References 105 publications

(81 reference statements)

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“…De Malo et al showed that the olfactory bulb is a conduit for viral entry into the brain [ 21 , 27 ]; thus, persistence of the virus in the olfactory bulb could explain the persistence of smell alteration. Other data are conflicting; Khan et al found that virus can affect the neuroepithelium without spreading into the olfactory bulbs [ 28 ]; however, the authors did not mention whether the patients suffered (or not) of smell disorders.…”

Section: Discussionmentioning

confidence: 99%

Olfactory Dysfunction, Headache, and Mental Clouding in Adults with Long-COVID-19: What Is the Link between Cognition and Olfaction? A Cross-Sectional Study

et al. 2022

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Smell alteration and cognitive impairment are common features of the Long-COVID Syndrome. Mental clouding, often described as brain fog, might affect smell by altering recollection of odors or through a share mechanism of neuroinflammation. We investigated mental clouding, headache, and cognitive function in adult patients with persistent COVID-19 olfactory dysfunction. This multi-center cross-sectional study enrolled 152 adults with self-reported olfactory dysfunction from 3 tertiary centers specialized in COVID-19 olfactory disorders. Inclusion criteria were smell alterations after COVID-19 persisting over 6 months from infection, age >18 and < 65. Exclusion criteria included smell alterations, headache, or memory problems prior to COVID-19 infection. The patients were evaluated by olfactometry, nasal endoscopy, headache scale, cognitive assessment, Mini Mental State Examination (MMSE), and self-reported measures. Smell dysfunction was stratified and classified based on olfactory deficit severity and presence of olfactory distortion (parosmia, cacosmia). Data on smell disorder, mental clouding, MMSE, and headache were analyzed to assess correlations. Among the 152 patients studied, 50 (32.8%) presented with anosmia, 25 (16.4%) with hyposmia, 10 (6.6%) with parosmia/cacosmia, and 58 patients (38.2%) with a combination of hyposmia and parosmia; seven (4.6%) patients suffered from headache exclusively, and two (1.4%) had headache and mental clouding as their primary symptom. Headache was reported by 76 (50%) patients, and mental clouding by 71 (46.7%). The patients reporting headache, mental clouding, or both, had significantly increased risk of suffering from anosmia and/or hyposmia when compared with their counterparts without these neurological symptoms. No patients had reduced MMSE scores. In our cohort of adult patients with post-COVID-19, smell alterations persisting over 6 months, cognitive impairment and headache were associated with more severe olfactory loss, consistent with neuroinflammatory mechanisms mediating a variety of Long-COVID symptoms.

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Section: Discussionmentioning

confidence: 99%

Olfactory Dysfunction, Headache, and Mental Clouding in Adults with Long-COVID-19: What Is the Link between Cognition and Olfaction? A Cross-Sectional Study

et al. 2022

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“…greater than 2 weeks 34 ) may bias towards analysis after virus is cleared. Human biopsies are also limited in their sample size and may miss important sites of infection-an explanation for negative findings supported by the fact that SARS-CoV-2 could not be detected in nasal epithelium or brain in more than half of individuals examined by a recent negative study 51 . In contrast, thorough examination of whole nasal cavity and brain from mice infected with a measured amount of virus at a known timepoints during a highly reproducible disease course enables detection of even transiently infected tissues.…”

Section: Discussionmentioning

confidence: 99%

“…However, SARS-CoV-2 neuronal infection has been refuted by prominent studies that failed to identify virus in the brains of deceased patients using methods such as single nuclear RNA sequencing 34 or RNA in situ hybridization and immunostaining of olfactory bulb neurons 51 . If infection of the OE and neighboring brain are associated with lethal COVID-19 disease, why is SARS-CoV-2 virus detected in human brain samples by some but not all investigators?…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 infection of olfactory epithelial cells and neurons drives acute lung injury and lethal COVID-19 in mice

Tang

Buchholz

Szigety

et al. 2021

Preprint

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Lethal COVID-19 is associated with respiratory failure that is thought to be caused by acute respiratory distress syndrome (ARDS) secondary to pulmonary infection. To date, the cellular pathogenesis has been inferred from studies describing the expression of ACE2, a transmembrane protein required for SARS-CoV-2 infection, and detection of viral RNA or protein in infected humans, model animals, and cultured cells. To functionally test the cellular mechanisms of COVID-19, we generated hACE2fl animals in which human ACE2 (hACE2) is expressed from the mouse Ace2 locus in a manner that permits cell-specific, Cre-mediated loss of function. hACE2fl animals developed lethal weight loss and hypoxemia within 7 days of exposure to SARS-CoV-2 that was associated with pulmonary infiltrates, intravascular thrombosis and patchy viral infection of lung epithelial cells. Deletion of hACE2 in lung epithelial cells prevented viral infection of the lung, but not weight loss, hypoxemia or death. Inhalation of SARS-CoV-2 by hACE2fl animals resulted in early infection of sustentacular cells with subsequent infection of neurons in the neighboring olfactory bulb and cerebral cortex, events that did not require lung epithelial cell infection. Pharmacologic ablation of the olfactory epithelium or Foxg1Cre mediated deletion of hACE2 in olfactory epithelial cells and neurons prevented lethality and neuronal infection following SARS-CoV-2 infection. Conversely, transgenic expression of hACE2 specifically in olfactory epithelial cells and neurons in Foxg1Cre; LSL-hACE2 mice was sufficient to confer neuronal infection associated with respiratory failure and death. These studies establish mouse loss and gain of function genetic models with which to genetically dissect viral-host interactions and demonstrate that lethal disease due to respiratory failure may arise from extrapulmonary infection of the olfactory epithelium and brain. Future therapeutic efforts focused on preventing olfactory epithelial infection may be an effective means of protecting against severe COVID-19.

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“…Inoculation of human pluripotent stem cell (hPSC)-derived brain organoids with SARS-CoV-2 revealed absent or mostly abortive infection of neurons and/or astrocytes, pointing towards the notion of limited neurotropism and replication in the CNS of SARS-CoV-2 ( Ramani et al, 2021 ). The frequent loss of smell and the high viral load in the olfactory epithelium of COVID-19 patients ( Meinhardt et al, 2021 ) brought the CNS entry route via axons of the olfactory receptor cells into focus, but this has not been confirmed ( Khan et al, 2021 ).…”

Section: Sars-cov-2mentioning

confidence: 99%

COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences

Martínez-Salazar

Holwerda

Stüdle

et al. 2022

Front. Cell Dev. Biol.

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first identified in December 2019 as a novel respiratory pathogen and is the causative agent of Corona Virus disease 2019 (COVID-19). Early on during this pandemic, it became apparent that SARS-CoV-2 was not only restricted to infecting the respiratory tract, but the virus was also found in other tissues, including the vasculature. Individuals with underlying pre-existing co-morbidities like diabetes and hypertension have been more prone to develop severe illness and fatal outcomes during COVID-19. In addition, critical clinical observations made in COVID-19 patients include hypercoagulation, cardiomyopathy, heart arrythmia, and endothelial dysfunction, which are indicative for an involvement of the vasculature in COVID-19 pathology. Hence, this review summarizes the impact of SARS-CoV-2 infection on the vasculature and details how the virus promotes (chronic) vascular inflammation. We provide a general overview of SARS-CoV-2, its entry determinant Angiotensin-Converting Enzyme II (ACE2) and the detection of the SARS-CoV-2 in extrapulmonary tissue. Further, we describe the relation between COVID-19 and cardiovascular diseases (CVD) and their impact on the heart and vasculature. Clinical findings on endothelial changes during COVID-19 are reviewed in detail and recent evidence from in vitro studies on the susceptibility of endothelial cells to SARS-CoV-2 infection is discussed. We conclude with current notions on the contribution of cardiovascular events to long term consequences of COVID-19, also known as “Long-COVID-syndrome”. Altogether, our review provides a detailed overview of the current perspectives of COVID-19 and its influence on the vasculature.

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Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb

Cited by 271 publications

References 105 publications

Olfactory Dysfunction, Headache, and Mental Clouding in Adults with Long-COVID-19: What Is the Link between Cognition and Olfaction? A Cross-Sectional Study

Olfactory Dysfunction, Headache, and Mental Clouding in Adults with Long-COVID-19: What Is the Link between Cognition and Olfaction? A Cross-Sectional Study

SARS-CoV-2 infection of olfactory epithelial cells and neurons drives acute lung injury and lethal COVID-19 in mice

COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences

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