Fig 1.
The blood–brain barrier tightly controls the transfer of solutes and cells between the lumen and the parenchyma.
Veins and arteries in the brain are tightly wrapped by vascular smooth muscle cells, while the endothelial cells of the capillaries are supported by the other cells of the neural vascular unit, including pericytes astrocytes, neurons, and microglia. Signals received from these cells by endothelial cells induce the expression of tight junction (claudin, occludin) and adherens junction (VE-cadherin) proteins. Homotypic interactions between junction proteins on neighboring endothelial cells keep brain endothelial cells closely adhered to each other and reduce paracellular permeability. Figure created using Biorender.
Fig 2.
Virus-infected pericytes impair brain endothelial cells and BBB function.
Brain pericytes are susceptible to infection by HIV, JEV, cytomegalovirus, and Zika virus. HIV enters pericytes through CCR5, CXCR4, or CD4. SARS-CoV-2 spike protein can trigger pericytes through the ACE-2 receptor. Once in the cells, viruses activate the NF-B pathway. JEV has also been shown to activate the ERK/CREB pathway through TLR7 and MyD88. NF-
B activity induces the secretion of cytokines such as IL-6, CCL5, and PGE2, which increase the permeability of the brain endothelium. IL-6 induces permeability by activiating UBR1 in brain endothelial cells, which marks the tight-junction protein occludin for degradation. While the invasion receptors and downstream pathways are not known, cytomegalovirus and zika virus can also reduce endothelial BBB function through the secretion of cytokines such as CXCL8, CXCL11, IL-6, IL-1
, TNF-
, CCL5, and TGF-
. HIV, Human Immunodeficiency Virus; JEV, Japanese Encephalitis Virus; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus-2; CCR-5, C-C chemokine receptor 5; CXCR4, C-X-C chemokine receptor type 4; CD4, cluster of differentiation 4; ACE-2, angiotensin converter enzyme 2; NF-
B, nuclear factor kappa B; ERK, extra-cellular signal-regulated kinase; CREB, cyclic adenosine monophosphate response element binding protein; TLR7, toll-like receptor 7; MYD88, Myeloid differentiation primary response protein 88; IL-6, interleukin 6; CCL-5, chemokine (C-C motif) ligand 5; PGE2, prostaglandin E2; UBR1, ubiquitin protein ligase E3 component n-recognin 1; CXCL8, interleukin-8; CXCL11, C-X-C motif chemokine ligand 11; IL-1
, interleukin-1 beta; TNF-
, tumor necrosis factor alpha; TGF-
, Transforming growth factor beta. Figure created using Biorender.
Table 1.
Markers of pericytes and their expression on other cells of the brain.