The pathways and the mechanisms by which Cryptococcus enters the brain

Abstract

Generally, Cryptococcus initially infects the respiratory tract, but can spread, eventually crossing the blood-brain barrier (BBB) and causing meningitis or meningoencephalitis. Specifically, Cryptococcus invades the vascular endothelial cells of the BBB, from which it enters the brain. The main mechanisms through which Cryptococcus crosses the BBB are transcellular traversal, the paracellular pathway, and via Trojan horse. In this paper, the mechanisms by which Cryptococcus crosses the BBB were explained in detail. In addition to pathways of entry to the brain, this paper presents a discussion on some rare cryptococcal infections and provides some insights for future research directions.

Keywords: Cryptococcus; blood-brain barrier; paracellular pathway; transcellular traversal; trojan horse mechanism.

Figure 1.

The pathways by which Cryptococcus result in infection. Cryptococcus were found in eucalyptus trees and pigeon droppings. Inhalation of cryptococcal basidiomycetes or yeast cells from the environment can cause pulmonary infection and meningitis. The intracranial infections originate from direct spread through bone defects and nerves, or indirect haematogenous diffusion, ultimately resulting in the pathogen crossing the blood-brain barrier (BBB) (By Figdraw).

Figure 2.

Anatomy and physiology of the blood-brain barrier (BBB) (By Figdraw).

Figure 3.

Model of transcellular traversal by which Cryptococcus crosses the blood-brain barrier (BBB). Cryptococci use host inositol which binds to their inositol transporter. Inositol is absorbed from the inositol transport tube on the cryptococcal cell membrane, followed by activating genes such as CPS1, which induces the expression of hyaluronic acid on the cryptococcal cell membrane. Hyaluronic acid binds to the CD44 receptor on the surface of HBMECs. Cryptococci induce EPH-EphrinA1 (EphA2) phosphorylation through transactivation of CD44, which promotes GTPase-dependent signalling. It induces the up-regulation of cytoskeleton-related proteins, reorganises the actin cytoskeleton, and internalises cryptococci via endocytosis. Cryptococci secrete metalloproteinase Mpr1, which binds to the Mpr1 target protein AnnexinA2 (AnxA2) inside the HBMECs. This also induces the up-regulation of cytoskeleton-related proteins, which triggers the reorganisation of actin cytoskeleton, thus cryptococci transcytosis and exit through HBMECs to cross BBB (By Figdraw).

Figure 4.

Model of the paracellular pathway by which Cryptococcus crosses the blood-brain barrier (BBB). (a) HBMEC was induced to secrete urokinase by Cryptococcus stimulation. Urokinase activates the conversion of plasminogen on the surface of cryptococci to plasmin, which degrades the fibrin-enriched extracellular matrix and basement membranes. This facilitates Cryptococcus to cross the BBB. (b) Cryptococcus secretes urease, which converts urea into ammonia. The local production of ammonia may damage endothelial cells, impair tight junctions, and widen endothelial cell gaps, thereby causing the migration of cryptococci into the brain (By Figdraw).

Figure 5.

Model of Trojan horse mechanism by which Cryptococcus crosses the blood-brain barrier (BBB). The phagocytosis of Cn inhibited the chemotaxis of macrophages stimulated by CX3CL1 and CSF-1. Phagocytes infected with Cryptococcus adhere to HBMEC and utilise their nuclear lobes to create gaps between (a) or within (b) endothelial cells. Nuclear lobes insert into the HBMEC gap, and then phagocytes enter the brain. Then cryptococci in phagocytes are carried to the side of the brain by this behaviour of phagocytes, and cryptococci continue to be wrapped in phagocytes or be released.