Central nervous system involvement by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2)

Paniz‐Mondolfi, Alberto; Bryce, Clare; Grimes, Zachary; Gordon, Ronald E.; Reidy, Jason; Lednicky, John A.; Sordillo, Emilia Mia; Fowkes, Mary

doi:10.1002/jmv.25915

Cited by 876 publications

(1,006 citation statements)

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“…They concluded that there was an active viral entry across the brain microvasculature into the neurons, as there was blebbing of viral particles coming in and out of the endothelial membrane. [35] Mechanistically, SARS-CoV2 virus may enter the CNS through hematogenous route or retrograde synaptic transmission. ACE 2 receptors, which are abundantly expressed in the endothelial cells, supporting glia and neurons, might be the binding site facilitating hematogenous entry.…”

Section: Discussionmentioning

confidence: 99%

Neurological Involvement of Coronavirus Disease 2019: A Systematic Review

Ghannam

Alshaer

Al-Chalabi

et al. 2020

Preprint

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Background: In December 2019, unexplained cases of pneumonia emerged in Wuhan, China, which were found to be secondary to the novel coronavirus SARS-CoV-2. On March 11, 2020, the WHO declared the Coronavirus Disease 2019 (COVID-2019) outbreak, a pandemic. Although the most common presentations of COVID-19 are fever, cough and shortness of breath, several clinical observations indicate that COVID-19 does affect the central and peripheral nervous system. Methods: We conducted a systematic literature search from December 01, 2019 to May 14, 2020 using multiple combinations of keywords from PubMed and Ovid Medline databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included articles with cases of COVID-19 that were evident for neurological involvement. Results: We were able to identify 82 cases of COVID-19 with neurological complications. The mean age was 62.28 years. 37.8% of the patients were women (n = 31). 48.8% of the patients (n=40) had cerebrovascular insults, 28% (n=23) had neuromuscular disorders, 18.3% of the patients (n=15) had encephalitis or encephalopathy, and 2.4% (n=2) presented with status epilepticus. Conclusions: Neurological manifestations of COVID-19 infection are not rare, especially large vessel stroke, Guillain barre syndrome and meningoencephalitis. Moving forward, further studies are needed to clarify the prevalence of the neurological complications of COVID-19, investigate their biological backgrounds, and test treatment options. Physicians should be cautious not to overlook other neurological diagnoses that can mimic COVID-19 during the pandemic.

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Section: Discussionmentioning

confidence: 99%

Neurological Involvement of Coronavirus Disease 2019: A Systematic Review

Ghannam

Alshaer

Al-Chalabi

et al. 2020

Preprint

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“…This expression suggests that SARS-CoV-2 could encounter its key binding target in the cerebrovasculature. Interestingly in Bryce et al, virus like particles were readily detectable by electron microscopy in the frontal lobe endothelium of a COVID-19 patient 38 .…”

Section: Whether Ace2 Expression Changes In Patients With Comorbiditimentioning

confidence: 94%

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood–brain barrier

Buzhdygan

DeOre

Baldwin‐Leclair

et al. 2020

Preprint

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As researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system includes neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report explored whether deleterious outcomes from the SARS-COV-2 viral spike protein on primary human brain microvascular endothelial cells (hBMVECs) could be observed. First, using postmortem brain tissue, we show that the angiotensin converting enzyme 2 or ACE2 (a known binding target for the SARS-CoV-2 spike protein), is expressed throughout various caliber vessels in the frontal cortex. Additionally, ACE2 was also detectable in primary human brain microvascular endothelial (hBMVEC) maintained under cell culture conditions. Analysis for cell viability revealed that neither the S1, S2 or a truncated form of the S1 containing only the RBD had minimal effects on hBMVEC viability within a 48hr exposure window. However, when the viral spike proteins were introduced into model systems that recapitulate the essential features of the Blood-Brain Barrier (BBB), breach to the barrier was evident in various degrees depending on the spike protein subunit tested. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluid model of the human BBB, a platform that most closely resembles the human physiological conditions at this CNS interface. Subsequent analysis also showed the ability for SARS-CoV-2 spike proteins to trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. Together, these results are the first to show the direct impact that the SARS-CoV-2 spike protein could have on brain endothelial cells; thereby offering a plausible explanation for the neurological consequences seen in COVID-19 patients.

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“…Additionally, many COVID-19 patients with severe disease do not respond well to artificial ventilation or display "silent hypoxia" (3), suggesting an extrapulmonary component to respiratory dysfunction, and cardiorespiratory function and fluid homeostasis are themselves subject to central nervous system (CNS) control. However, despite emerging reports of the post-mortem detection of the virus in the cerebrospinal fluid (CSF) (see for example (4)) or brain parenchyma of patients (5), little is known about how and under what circumstances SARS-CoV-2 infects the brain.…”

Section: Main Textmentioning

confidence: 99%

The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

Nampoothiri

Sauvé

Ternier

et al. 2020

Preprint

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Most patients with COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), display neurological symptoms, and respiratory failure in certain cases could be of extrapulmonary origin. Hypothalamic neural circuits play key roles in sex differences, diabetes, hypertension, obesity and aging, all risk factors for severe COVID-19, besides being connected to olfactory/gustative and brainstem cardiorespiratory centers. Here, human brain gene-expression analyses and immunohistochemistry reveal that the hypothalamus and associated regions express angiotensin-converting enzyme 2 and transmembrane proteinase, serine 2, which mediate SARS-CoV-2 cellular entry, in correlation with genes or pathways involved in physiological functions or viral pathogenesis. A post-mortem patient brain shows viral invasion and replication in both the olfactory bulb and the hypothalamus, while animal studies indicate that sex hormones and metabolic diseases influence this susceptibility. Main textSARS-CoV-2 infection is increasingly associated with a wide range of neurological symptomsheadaches, dizziness, nausea, loss of consciousness, seizures, encephalitis etc., as well as anosmia or ageusia -in the majority of patients (1,2). Additionally, many COVID-19 patients with severe disease do not respond well to artificial ventilation or display "silent hypoxia" (3), suggesting an extrapulmonary component to respiratory dysfunction, and cardiorespiratory function and fluid homeostasis are themselves subject to central nervous system (CNS) control. However, despite emerging reports of the post-mortem detection of the virus in the cerebrospinal fluid (CSF) (see for example (4)) or brain parenchyma of patients (5), little is known about how and under what circumstances SARS-CoV-2 infects the brain.While the possibility of CNS infection has been largely underestimated due to the common view that angiotensin converting enzyme 2 (ACE2), the only confirmed cellular receptor for SARS-CoV-2 so far (6), is absent or expressed only at very low levels in the brain (7,8), and that too exclusively in vascular cells (He et al., bioRxiv 2020; doi: https://doi.org/10.1101.088500) the majority of these studies have focused on the cerebral cortex, ignoring the fact that other regions such as the hypothalamus, are rich in ACE2 (9). Intriguingly, most major risk factors for severe COVID-19 (male sex, age, obesity, hypertension, diabetes); reviewed by (10,11); could be mediated by normal or dysfunctional hypothalamic neural networks that regulate a variety of physiological processes: sexual differentiation and gonadal hormone production, energy homeostasis, fluid homeostasis/osmoregulation and even ageing (12)(13)(14). The hypothalamus is also directly linked to other parts of the CNS involved in functions affected in COVID-19 patients, including brainstem nuclei that control fluid homeostasis, cardiac function and respiration, as well as regions implicated in the perception or integration of odor and taste (12,(14)(15)(16)(17)(18).Here, we inves...

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Central nervous system involvement by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2)

Cited by 876 publications

References 19 publications

Neurological Involvement of Coronavirus Disease 2019: A Systematic Review

Neurological Involvement of Coronavirus Disease 2019: A Systematic Review

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood–brain barrier

The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

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