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

Sousa, Antônio Kleiton de; Magalhães, Diva de Aguiar; Ferreira, Jayro dos Santos; Barbosa, André Luiz dos Reis

doi:10.1016/j.mehy.2020.110213

Cited by 22 publications

(23 citation statements)

References 44 publications

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“…Our assumption of apoptosis due to increased percentage of AGTR2+ cells is supported by an earlier study on an intestinal epithelial cell line (Caco-2) where the induction of epithelial cell apoptosis could be triggered by the activation of AGTR2 through GATA-6 and the Bax signaling pathway (27). AGTR2 has also recently been shown to be a potential coreceptor for SARS-CoV-2 entry in various human cells, including those of the central nervous system (98,99). Therefore, an increased expression of AGTR2+ cells in gut tissues during infection may promote increased susceptibility to SARS-CoV-2 infection.…”

Section: Discussionsupporting

confidence: 77%

Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques

et al. 2022

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Angiotensin converting enzyme-2 (ACE2) and associated proteins play a pivotal role in various physiological and pathological events, such as immune activation, inflammation, gut barrier maintenance, intestinal stem cell proliferation, and apoptosis. Although many of these clinical events are quite significant in SIV/HIV infection, expression profiling of these proteins has not been well reported. Considering the different pathological consequences in the gut after HIV infection, we hypothesized that the expression of ACE2 and associated proteins of the Renin-angiotensin system (RAS) could be compromised after SIV/HIV infection. We quantified the gene expression of ACE2 as well as AGTR1/2, ADAM17, and TMPRSS2, and compared between SIV infected and uninfected rhesus macaques (Macaca mulatta; hereafter abbreviated RMs). The gene expression analysis revealed significant downregulation of ACE2 and upregulation of AGTR2 and inflammatory cytokine IL-6 in the gut of infected RMs. Protein expression profiling also revealed significant upregulation of AGTR2 after infection. The expression of ACE2 in protein level was also decreased, but not significantly, after infection. To understand the entirety of the process in newly regenerated epithelial cells, a global transcriptomic study of enteroids raised from intestinal stem cells was performed. Interestingly, most of the genes associated with the RAS, such as DPP4, MME, ANPEP, ACE2, ENPEP, were found to be downregulated in SIV infection. HNFA1 was found to be a key regulator of ACE2 and related protein expression. Jejunum CD4+ T cell depletion and increased IL-6 mRNA, MCP-1 and AGTR2 expression may signal inflammation, monocyte/macrophage accumulation and epithelial apoptosis in accelerating SIV pathogenesis. Overall, the findings in the study suggested a possible impact of SIV/HIV infection on expression of ACE2 and RAS-associated proteins resulting in the loss of gut homeostasis. In the context of the current COVID-19 pandemic, the outcome of SARS-CoV-2 and HIV co-infection remains uncertain and needs further investigation as the significance profile of ACE2, a viral entry receptor for SARS-CoV-2, and its expression in mRNA and protein varied in the current study. There is a concern of aggravated SARS-CoV-2 outcomes due to possible serious pathological events in the gut resulting from compromised expression of RAS- associated proteins in SIV/HIV infection.

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Section: Discussionsupporting

confidence: 77%

Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques

et al. 2022

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“…It is well known that, among other targets, SARS-CoV-2 has a strong neuroinvasive capacity causing multiple neurological symptoms [ 4 ] with increased blood–brain barrier (BBB) damage and neuroinflammation [ 5 ]. There are some indications, however, that not only the SARS-CoV-2 virus but also its S1 spike glycoprotein alone may be responsible for a major part of these problems [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Penetration of the SARS-CoV-2 Spike Protein across the Blood–Brain Barrier, as Revealed by a Combination of a Human Cell Culture Model System and Optical Biosensing

et al. 2022

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Since the outbreak of the global pandemic caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), several clinical aspects of the disease have come into attention. Besides its primary route of infection through the respiratory system, SARS-CoV-2 is known to have neuroinvasive capacity, causing multiple neurological symptoms with increased neuroinflammation and blood–brain barrier (BBB) damage. The viral spike protein disseminates via circulation during infection, and when reaching the brain could possibly cross the BBB, which was demonstrated in mice. Therefore, its medical relevance is of high importance. The aim of this study was to evaluate the barrier penetration of the S1 subunit of spike protein in model systems of human organs highly exposed to the infection. For this purpose, in vitro human BBB and intestinal barrier cell–culture systems were investigated by an optical biosensing method. We found that spike protein crossed the human brain endothelial cell barrier effectively. Additionally, spike protein passage was found in a lower amount for the intestinal barrier cell layer. These observations were corroborated with parallel specific ELISAs. The findings on the BBB model could provide a further basis for studies focusing on the mechanism and consequences of spike protein penetration across the BBB to the brain.

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“…Once attached, the host infection requires the expression of transmembrane serine protease 2 (TMPRSS2) for priming of the spike protein and viral entry into the cell [ 20 – 22 ]. Along with ACE2 and TMPRSS2, several other molecules have been suggested to participate in SARS-CoV-2 entry into human cells, such as ADAM metallopeptidase domain 17 (ADAM17) [ 23 , 24 ], dipeptidyl peptidase 4 (DPP4) [ 25 , 26 ], angiotensin II receptor type 2 (AGTR2) [ 27 , 28 ], basigin (BSG, also called extracellular matrix metalloproteinase inducer [EMMPRIN] or cluster of differentiation 147 [CD147]) [ 19 , 29 ], aminopeptidase N (ANPEP), [ 30 ], and cathepsin B/L [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Expression of SARS-CoV-2-related receptors in cells of the neurovascular unit: implications for HIV-1 infection

Torices

Cabrera

Stangis

et al. 2021

J Neuroinflammation

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Background Neurological complications are common in patients affected by COVID-19 due to the ability of SARS-CoV-2 to infect brains. While the mechanisms of this process are not fully understood, it has been proposed that SARS-CoV-2 can infect the cells of the neurovascular unit (NVU), which form the blood-brain barrier (BBB). The aim of the current study was to analyze the expression pattern of the main SARS-CoV-2 receptors in naïve and HIV-1-infected cells of the NVU in order to elucidate a possible pathway of the virus entry into the brain and a potential modulatory impact of HIV-1 in this process. Methods The gene and protein expression profile of ACE2, TMPRSS2, ADAM17, BSG, DPP4, AGTR2, ANPEP, cathepsin B, and cathepsin L was assessed by qPCR, immunoblotting, and immunostaining, respectively. In addition, we investigated if brain endothelial cells can be affected by the exposure to the S1 subunit of the S protein, the domain responsible for the direct binding of SARS-CoV-2 to the ACE2 receptors. Results The receptors involved in SARS-CoV-2 infection are co-expressed in the cells of the NVU, especially in astrocytes and microglial cells. These receptors are functionally active as exposure of endothelial cells to the SARS CoV-2 S1 protein subunit altered the expression pattern of tight junction proteins, such as claudin-5 and ZO-1. Additionally, HIV-1 infection upregulated ACE2 and TMPRSS2 expression in brain astrocytes and microglia cells. Conclusions These findings provide key insight into SARS-CoV-2 recognition by cells of the NVU and may help to develop possible treatment of CNS complications of COVID-19.

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

Cited by 22 publications

References 44 publications

Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques

Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques

Penetration of the SARS-CoV-2 Spike Protein across the Blood–Brain Barrier, as Revealed by a Combination of a Human Cell Culture Model System and Optical Biosensing

Expression of SARS-CoV-2-related receptors in cells of the neurovascular unit: implications for HIV-1 infection

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