How Cryptococcus Interacts with the Blood–Brain Barrier

Abstract

Cryptococcus demonstrates predilection for invasion of the brain, but the mechanism by which Cryptococcus crosses the blood-brain barrier (BBB) to cause brain invasion is largely unknown. In order for Cryptococcus to cross the BBB, there must be a way to either cross human brain microvascular endothelial cells, which are the main constitute of the BBB, or go in between tight junctions. Recent evidence of human brain microvascular endothelial cell responses to transcellular brain invasions includes membrane rearrangements, intracellular signaling pathways and cytoskeletal activations. Several Cryptococcal genes related to the traversal of BBB have been identified, including CPS1, ITR1a, ITR3c, PLB1, MPR1, FNX1 and RUB1. In addition, Cryptococcus neoformans-derived microvesicles may contribute to cryptococcal brain invasion. Paracellularly, Cryptococcus may traverse across BBB using either routes utilizing plasmin, ammonia or macrophages in a Trojan horse mechanism.

Ibrutinib‐associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non‐Hodgkin lymphoma: An observational study

“…Btk signalling also regulates the development and a range of effector functions of myeloid cells, including chemotaxis, adhesion, transmigration, reactive oxygen species production and cytokine response . This may allude to the Trojan horse hypothesis put forward by Tseng et al regarding the possible mechanisms used by Cryptococcus to cross the blood‐brain barrier . Comparably, ibrutinib‐paralysed macrophages may transport fungal spores into the CNS facilitating infection.…”

“…11 This may allude to the Trojan horse hypothesis put forward by Tseng et al regarding the possible mechanisms used by Cryptococcus to cross the blood-brain barrier. 34 Comparably, ibrutinib-paralysed macrophages may transport fungal spores into the CNS facilitating infection.…”

Mechanisms of Pulmonary Escape and Dissemination by Cryptococcus neoformans

“…There are two main routes by which C. neoformans is predicted to escape the lungs and invade deeper tissues ( Figure 1 ). The first is an intracellular route within macrophages or other phagocytes migrating out from the lungs, known as the “Trojan horse” mechanism [ 21 , 22 ]. The second is the escape of extracellular C. neoformans cells.…”

“…Little is known about how C. neoformans might enter and transverse respiratory epithelial cells after adhesion, a process known as transcytosis [ 66 , 67 ]. Transcytosis also occurs when C. neoformans cells cross the blood–brain barrier [ 21 ]. However, the frequency and relevance of respiratory epithelial cell transcytosis during infection is unclear.…”

“…Before C. neoformans can invade deeper tissues of the host, such as the CNS, it must first escape from the lungs. Additionally, the state of C. neoformans exiting the lungs can influence later stages in dissemination, such as transversal of the blood–brain barrier [ 21 ]. In this review, we explore processes leading to C. neoformans ’s escape from the lungs and dissemination throughout the host.…”