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

Abstract

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.

TOM70 in Glial Cells as a Potential Target for Treatment of COVID-19

“…It has been proposed that the neuroinvasion of SARS-CoV-2 through the BBB may occur via interaction of the viral spike protein with ACE2 expressed in the capillary endothelium, subsequently infecting CNS cells, including glia (Jha et al, 2021). Consistent with this, the receptors involved in SARS-CoV-2 infection including ACE2 were seen to be expressed in the cells of the neurovascular unit, especially in astrocytes and microglial cells (Torices et al, 2021). Recent studies also showed that human pericyte-like cells from brain organoids and endothelial cells from mouse cerebral microvessels can be infected by SARS-CoV-2 (Wang et al, 2021;Wenzel et al, 2021).…”

Comprehensive Oncogenic Features of Coronavirus Receptors in Glioblastoma Multiforme

“…In addition to ACE2 and TMPRSS2 , several other molecules have also been suggested to participate in SARS-CoV-2 cell entry, such as DPP4 , ANPEP , AXL , and ENPEP ( 30 – 41 ). ACE2 is detected in the CNS, namely, substantia nigra and brain ventricles, piriform cortex, neurons and some nonneuronal cells (astrocytes and oligodendrocytes from the middle temporal gyrus and posterior cingulate cortex) ( 52 – 54 ). TMPRSS2 is observed in oligodendrocyte precursor cells, astrocytes and microglial cells of the neurovascular units ( 53 , 54 ).…”

“…ACE2 is detected in the CNS, namely, substantia nigra and brain ventricles, piriform cortex, neurons and some nonneuronal cells (astrocytes and oligodendrocytes from the middle temporal gyrus and posterior cingulate cortex) ( 52 – 54 ). TMPRSS2 is observed in oligodendrocyte precursor cells, astrocytes and microglial cells of the neurovascular units ( 53 , 54 ). DPP4 and ANPEP are distributed in astrocytes and microglial cells of neurovascular units ( Table 1 ) ( 54 ).…”

Altered Expression of ACE2 and Co-receptors of SARS-CoV-2 in the Gut Mucosa of the SIV Model of HIV/AIDS

“…Several studies have identified that co-infection with SARS-CoV-2 and influenza A led to increased pathological outcomes in animal models and human patients ( Alosaimi et al, 2021 ; Yang et al, 2021 ; Zhao et al, 2021 ). Increased expression of receptors for SARS-CoV-2, ACE2 and TMPRSS2, in human neuronal cells and microglia is reported in HIV infection ( Torices et al, 2021 ). Our study demonstrated a trend of enhanced expression of ACE2 in the gut epithelial lining in the villi during SIV infection in vivo , resulting in availability of abundant binding sites for SARS-CoV-2.…”