Neuroinvasion of SARS-CoV-2 in human and mouse brain

The Journal of Experimental Medicine, Journal Year: 2021, Volume and Issue: 218(3)

Published: Jan. 12, 2021

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there no consensus on consequences of CNS infections. Here, we used three independent approaches probe capacity infect brain. First, using human brain organoids, observed clear evidence infection with accompanying metabolic changes in infected and neighboring neurons. However, for type I interferon responses was detected. We demonstrate that neuronal can prevented by blocking ACE2 antibodies or administering cerebrospinal fluid from patient. Second, mice overexpressing ACE2, neuroinvasion vivo. Finally, autopsies patients who died COVID-19, detect cortical neurons note pathological features associated minimal immune cell infiltrates. These results provide neuroinvasive an unexpected consequence direct SARS-CoV-2.

Language: Английский

---

Dysregulation of brain and choroid plexus cell types in severe COVID-19

Nature, Journal Year: 2021, Volume and Issue: 595(7868), P. 565 - 571

Published: June 21, 2021

Language: Английский

---

SARS-CoV-2 Infects the Brain Choroid Plexus and Disrupts the Blood-CSF Barrier in Human Brain Organoids

Cell stem cell, Journal Year: 2020, Volume and Issue: 27(6), P. 951 - 961.e5

Published: Oct. 13, 2020

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, leads to symptoms that can be fatal. However, neurological have also been observed in some patients. The cause of these complications is currently unknown. Here, we use human-pluripotent-stem-cell-derived brain organoids examine SARS-CoV-2 neurotropism. We find expression viral receptor ACE2 mature choroid plexus cells expressing abundant lipoproteins, but not neurons or other cell types. challenge with spike pseudovirus and live virus demonstrate tropism for epithelial little no infection glia. infected are apolipoprotein- ACE2-expressing barrier. Finally, show damages epithelium, leading leakage across this important barrier normally prevents entry pathogens, immune cells, cytokines into cerebrospinal fluid brain.

Language: Английский

---

The Spatial and Cell-Type Distribution of SARS-CoV-2 Receptor ACE2 in the Human and Mouse Brains

Frontiers in Neurology, Journal Year: 2021, Volume and Issue: 11

Published: Jan. 20, 2021

By engaging angiotensin-converting enzyme 2 (ACE2 or Ace2), the novel pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV-2) invades host cells and affects many organs, including brain. However, distribution of ACE2 in brain is still obscure. Here, we investigated expression by analyzing data from publicly available transcriptome databases. According to our spatial analysis, was relatively highly expressed some locations, such as choroid plexus paraventricular nuclei thalamus. cell-type nuclear found neurons (both excitatory inhibitory neurons) non-neuron (mainly astrocytes, oligodendrocytes, endothelial cells) human middle temporal gyrus posterior cingulate cortex. A few ACE2-expressing were a hippocampal dataset, none detected prefrontal Except for additional high Ace2 olfactory bulb areas well pericytes distribution, mouse similar that Thus, results reveal an outline ACE2/Ace2 brains, which indicates infection SARS-CoV-2 may be capable inducing central nervous system symptoms disease 2019 (COVID-19) patients. Potential species differences should considered when using models study neurological effects infection.

Language: Английский

---

Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction

Cell stem cell, Journal Year: 2020, Volume and Issue: 27(6), P. 890 - 904.e8

Published: Oct. 21, 2020

Language: Английский

---

Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(21)

Published: May 6, 2021

Prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and recurrence PCR-positive tests have been widely reported in patients after recovery from COVID-19, but some these do not appear to shed infectious virus. We investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed integrated into DNA human cells culture transcription sequences might account for positive PCR seen patients. In support this hypothesis, we found copies genome infected cells. target site duplications flanking viral consensus LINE1 endonuclease recognition at integration sites, consistent with a retrotransposon-mediated, target-primed reverse retroposition mechanism. also found, patient-derived tissues, evidence suggesting large fraction is transcribed sequences, generating viral-host chimeric transcripts. The may thus contribute by infection clinical recovery. Because detected only subgenomic derived mainly 3' end host cell, virus cannot produced sequences.

Language: Английский

---

SARS-CoV-2 crosses the blood–brain barrier accompanied with basement membrane disruption without tight junctions alteration

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Sept. 6, 2021

Abstract SARS-CoV-2 has been reported to show a capacity for invading the brains of humans and model animals. However, it remains unclear whether how crosses blood–brain barrier (BBB). Herein, RNA was occasionally detected in vascular wall perivascular space, as well brain microvascular endothelial cells (BMECs) infected K18-hACE2 transgenic mice. Moreover, permeability vessel increased. Furthermore, disintegrity BBB discovered hamsters by administration Evans blue. Interestingly, expression claudin5, ZO-1, occludin ultrastructure tight junctions (TJs) showed unchanged, whereas, basement membrane disrupted Using an vitro that comprises primary BMECs with astrocytes, found infect cross through BMECs. Consistent vivo experiments, MMP9 increased collagen IV decreased while markers TJs were not altered SARS-CoV-2-infected Besides, inflammatory responses including vasculitis, glial activation, upregulated factors occurred after infection. Overall, our results provide evidence supporting can transcellular pathway accompanied without obvious alteration TJs.

Language: Английский

---

Three-Dimensional Human Alveolar Stem Cell Culture Models Reveal Infection Response to SARS-CoV-2

Cell stem cell, Journal Year: 2020, Volume and Issue: 27(6), P. 905 - 919.e10

Published: Oct. 21, 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the cause of a present pandemic, infects human lung alveolar type (hAT2) cells. Characterizing pathogenesis crucial for developing vaccines and therapeutics. However, lack models mirroring cellular physiology pathology hAT2 cells limits study. Here, we develop feeder-free, long-term, three-dimensional (3D) culture technique derived from primary tissue investigate infection response to SARS-CoV-2. By imaging-based analysis single-cell transcriptome profiling, reveal rapid viral replication increased expression interferon-associated genes proinflammatory in infected cells, indicating robust endogenous innate immune response. Further tracing mutations acquired during transmission identifies full individual effectively single entry. Our study provides deep insights into SARS-CoV-2 application defined 3D cultures as diseases.

Language: Английский

---

Morphological, cellular, and molecular basis of brain infection in COVID-19 patients

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(35)

Published: Aug. 11, 2022

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum cerebral impact acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranging from alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to damage confirmed brain tissue samples extracted orbitofrontal region (via endonasal transethmoidal access) who died COVID-19. In an independent cohort 26 COVID-19, we used histopathological signs a guide for possible SARS-CoV-2 infection found that among 5 exhibited those signs, all them had genetic material virus brain. Brain these five patients also foci replication, particularly astrocytes. Supporting hypothesis astrocyte neural stem cell-derived human astrocytes vitro are susceptible through noncanonical mechanism involves spike-NRP1 interaction. SARS-CoV-2-infected manifested changes energy metabolism key proteins metabolites fuel neurons, well biogenesis neurotransmitters. Moreover, elicits secretory phenotype reduces neuronal viability. Our data support model which reaches brain, infects astrocytes, consequently, leads death or dysfunction. These deregulated processes could contribute structural functional seen brains patients.

Language: Английский

---

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Cell stem cell, Journal Year: 2021, Volume and Issue: 29(2), P. 217 - 231.e8

Published: Dec. 25, 2021

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells associated with increased tubule-interstitial fibrosis in patient autopsy samples. To study effects virus on independent systemic infected human-induced pluripotent stem-cell-derived organoids SARS-CoV-2. Single-cell RNA sequencing indicated injury dedifferentiation activation profibrotic signaling pathways. Importantly, infection also led to collagen 1 protein expression organoids. A protease inhibitor was able ameliorate by Our results suggest can infect induce cell subsequent fibrosis. These data could explain both acute COVID-19 patients development chronic disease long COVID.

Language: Английский

---