Mechanisms of microbial traversal of the blood-brain barrier

Abstract

Central nervous system (CNS) infections continue to be an important cause of morbidity and mortality. Microbial invasion and traversal of the blood-brain barrier is a prerequisite for CNS infections. Pathogens can cross the blood-brain barrier transcellularly, paracellularly and/or in infected phagocytes (the so-called Trojan-horse mechanism). Consequently, pathogens can cause blood-brain barrier dysfunction, including increased permeability, pleocytosis and encephalopathy. A more complete understanding of the microbial-host interactions that are involved in microbial traversal of the blood-brain barrier and the associated barrier dysfunction should help to develop new strategies to prevent CNS infections.

Figure 1. The blood–brain barrier

The blood–brain barrier is formed by brain microvascular endothelial cells, astrocytes and pericytes. It maintains the neural microenvironment by regulating the passage of molecules into and out of the brain, and protects the brain from any microorganisms and toxins that are circulating in the blood.

Figure 2. Mechanisms involved in microbial traversal of the blood–brain barrier

Pathogens can cross the blood–brain barrier transcellularly, paracellularly and/or in infected phagocytes (the Trojan-horse mechanism). a | In transcellular traversal, the pathogens cross the barrier without any evidence of intercellular tight-junction disruption or detection of microorganisms between cells. b | Paracellular traversal involves microbial penetration between barrier cells with and/or without evidence of tight-junction disruption. c | The Trojan-horse mechanism involves microbial penetration of the barrier cells using transmigration within infected phagocytes.

Figure 3. The effect of microbial determinants on Escherichia coli meningitis

In infant rats with experimental haematogenous E. coli meningitis, isogenic mutants of E. coli K1 strain RS218 in which outer-membrane protein A (OmpA), IbeA, IbeB, IbeC, arylsulfatase-like protein (AslA) and cytotoxic necrotizing factor 1 (CNF1) had been deleted were less able to traverse the blood–brain barrier and cause meningitis than the parental strain, despite causing similar levels of bacteraemia. CFU, colony-forming unit.

Figure 4. Signalling mechanisms involved in Escherichia coli K1-mediated actin cytoskeleton rearrangements and traversal of the blood–brain barrier

E. coli K1 invasion and traversal of the blood–brain barrier occurs as the result of specific bacterial interactions with receptors (CD48, gp96, R and LR) on brain microvascular endothelial cells (BMECs) and involves FAK, paxillin, phosphatidylinositol 3-kinase, Rho GTPases, 5-LO and cPLA2α. 5-LO, 5-lipoxygenase; CNF1, cytotoxic necrotizing factor 1; cPLA2α, cytosolic phospholipase A2α; FAK, focal adhesion kinase; gp96, glycoprotein 96; OmpA, outer-membrane protein A; PH, pleckstrin homology; PIP, phosphatidylinositol phosphate.