Dataset Information

SARS-CoV-2-mediated encephalitis: Role of AT2R receptors in the blood-brain barrier.

ABSTRACT: At the end of 2019, there was an outbreak of a new Coronavirus 2019 (COVID-19 disease). Studies suggest that SARS-CoV-2 can cause infection in the central nervous system (CNS) and trigger neurological symptoms that include headache, nausea and vomiting, mental confusion and loss of smell or taste. These findings reveal that Coronaviruses have neurological tropism and neuroinvasive capacity. The spread of SARS-CoV-2 in the brain tissue possibly occurs through the systemic circulation as reported in patients affected by SARS-CoV. Evidence highlights similarity between the SARS-CoV genome and SARS-CoV-2 and that both interact with the angiotensin-converting enzyme type 2 (ACE2) located in the brain tissue of infected patients. Hence, the presence of ACE2 is likely in the CNS to mediate the entry of the SARS-CoV-2 virus into neural tissue. Our hypothesis suggests that SARS-CoV-2 can cause encephalitis through the production of inflammatory mediators and activation of immune system cells resulting from the interaction of the ACE2 receptor with the viral Spike protein that causes an increase in angiotensin II. This mechanism has the ability to activate immune system cells by exacerbating stimuli at the angiotensin 2 receptor (AT2R). Thus, it leads to a status of brain injury preceded by vascular damage and destruction of the blood-brain barrier, making it responsible for the installation of acute inflammation.

SUBMITTER: de Sousa AK

PROVIDER: S-EPMC7449115 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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SARS-CoV-2-mediated encephalitis: Role of AT2R receptors in the blood-brain barrier.

de Sousa Antônio Kleiton AK Magalhães Diva de Aguiar DA Ferreira Jayro Dos Santos JDS Barbosa André Luiz Dos Reis ALDR

Medical hypotheses 20200826

At the end of 2019, there was an outbreak of a new Coronavirus 2019 (COVID-19 disease). Studies suggest that SARS-CoV-2 can cause infection in the central nervous system (CNS) and trigger neurological symptoms that include headache, nausea and vomiting, mental confusion and loss of smell or taste. These findings reveal that Coronaviruses have neurological tropism and neuroinvasive capacity. The spread of SARS-CoV-2 in the brain tissue possibly occurs through the systemic circulation as reported ...[more]

PMID: 33254519

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Project description:BackgroundAs a consequence of SARS-CoV-2 infection various neurocognitive and neuropsychiatric symptoms can appear, which may persist for several months post infection. However, cell type-specific routes of brain infection and underlying mechanisms resulting in neuroglial dysfunction are not well understood.MethodsHere, we investigated the susceptibility of cells constituting the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus (ChP) to SARS-CoV-2 infection using human induced pluripotent stem cell (hiPSC)-derived cellular models and a ChP papilloma-derived epithelial cell line as well as ChP tissue from COVID-19 patients, respectively.ResultsWe noted a differential infectibility of hiPSC-derived brain microvascular endothelial cells (BMECs) depending on the differentiation method. Extended endothelial culture method (EECM)-BMECs characterized by a complete set of endothelial markers, good barrier properties and a mature immune phenotype were refractory to SARS-CoV-2 infection and did not exhibit an activated phenotype after prolonged SARS-CoV-2 inoculation. In contrast, defined medium method (DMM)-BMECs, characterized by a mixed endothelial and epithelial phenotype and excellent barrier properties were productively infected by SARS-CoV-2 in an ACE2-dependent manner. hiPSC-derived brain pericyte-like cells (BPLCs) lacking ACE2 expression were not susceptible to SARS-CoV-2 infection. Furthermore, the human choroid plexus papilloma-derived epithelial cell line HIBCPP, modeling the BCSFB was productively infected by SARS-CoV-2 preferentially from the basolateral side, facing the blood compartment. Assessment of ChP tissue from COVID-19 patients by RNA in situ hybridization revealed SARS-CoV-2 transcripts in ChP epithelial and ChP stromal cells.ConclusionsOur study shows that the BCSFB of the ChP rather than the BBB is susceptible to direct SARS-CoV-2 infection. Thus, neuropsychiatric symptoms because of COVID-19 may rather be associated with dysfunction of the BCSFB than the BBB. Future studies should consider a role of the ChP in underlying neuropsychiatric symptoms following SARS-CoV-2 infection.

Project description:Autoimmune encephalitis (AE) is a severe neurological disease. The brain of the AE patient is attacked by a dysregulated immune system, which is caused by the excessive production of autoantibodies against neuronal receptors and synaptic proteins. AE is also characterized by the uncontrolled B lymphocyte infiltration through the blood-brain barrier (BBB) layer, and the investigation of the underlying mechanism involved in this infiltration may facilitate the discovery of novel therapies for AE. However, few AE-related studies have focused on this issue. In this study, we aimed to identify the factors involved in B lymphocyte infiltration in AE. For this purpose, we first enrolled four healthy control and five AE subjects, collecting their serum and/or total white blood cell samples. The white blood cell samples were further used for collecting RNA and DNA. Then, we simulated the in vivo B lymphocyte infiltration with an in vitro leukocyte transendothelial migration model. It turned out that AE serum treatment significantly and specifically promoted B cells to penetrate the BBB endothelial layer without affecting neutrophils. Next, through genome-wide DNA methylation assays on bisulfite-conversion DNA samples, we identified S100A6 and S100A11 as potential hypo-methylated disease genes in the AE samples. Further qPCR assays demonstrated their upregulation in AE samples, reflecting the negative correlations between gene expression and DNA methylation. Finally, recombinant S100A6 protein treatment significantly increased B lymphocyte infiltration through the BBB endothelial layer, which partially recapitulated the effect of AE serum. In summary, by using an in vitro leukocyte transendothelial migration model, we confirmed that S100A6 promoted B lymphocyte to penetrate the BBB endothelial layer, which is similar to the in vivo clinical manifestations of AE. Therefore, further studies on how the S100A6 protein facilitates B lymphocyte infiltration and on whether other factors in serum also contribute to this phenomenon are likely to improve our understanding of AE and hopefully to reveal novel therapeutic targets for this emerging treatable neurological disorder.

Dataset Information

SARS-CoV-2-mediated encephalitis: Role of AT2R receptors in the blood-brain barrier.

Publications

SARS-CoV-2-mediated encephalitis: Role of AT2R receptors in the blood-brain barrier.

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