Cryptococcal Yeast Cells Invade the Central Nervous System via Transcellular Penetration of the Blood-Brain Barrier

Chang, Yun C.; Stins, Monique F.; McCaffery, Michael J.; Miller, Georgina; Pare, Dan R.; Dam, Tapen; Paul-Satyasee, Maneesh; Kim, Kwang Sik; Kwon‐Chung, Kyung J.

doi:10.1128/iai.72.9.4985-4995.2004

Cited by 237 publications

(234 citation statements)

References 44 publications

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“…These results support the hypothesis that C. neoformans traverses the blood-brain barrier following a "transcellular pathway." A scanning electron microscopic study has shown that microvilli and membrane extension embraced C. neoformans during its internalization, suggesting that C. neoformans invasion of HBMEC utilizes a "zipper-like mechanism" in which the host cell plasma membrane enwraps the invading yeast (36). This mechanism therefore requires C. neoformans cell-induced HBMEC cytoskeletal rearrangements to accumulate actin fibers at the site of C. neoformans entry.…”

Section: Discussionmentioning

confidence: 99%

Invasion of Cryptococcus neoformans into Human Brain Microvascular Endothelial Cells Is Mediated through the Lipid Rafts-Endocytic Pathway via the Dual Specificity Tyrosine Phosphorylation-regulated Kinase 3 (DYRK3)

Huang

Long

et al. 2011

Journal of Biological Chemistry

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Cryptococcus neoformans is a neurotropic fungal pathogen, which provokes the onset of devastating meningoencephalitis. We used human brain microvascular endothelial cells (HBMEC) as the in vitro model to investigate how C. neoformans traverses across the blood-brain barrier. In this study, we present several lines of evidence indicating that C. neoformans invasion is mediated through the endocytic pathway via lipid rafts. Human CD44 molecules from lipid rafts can directly interact with hyaluronic acid, the C. neoformans ligand. Bikunin, which perturbs CD44 function in the lipid raft, can block C. neoformans adhesion and invasion of HBMEC. The lipid raft marker, ganglioside GM1, co-localizes with CD44 on the plasma membrane, and C. neoformans cells can adhere to the host cell in areas where GM1 is enriched. These findings suggest that C. neoformans entry takes place on the lipid rafts. Upon C. neoformans engagement, GM1 is internalized through vesicular structures to the nuclear membrane. This endocytic redistribution process is abolished by cytochalasin D, nocodazole, or anti-DYRK3 (dual specificity tyrosine-phosphorylation-regulated kinase 3) siRNA. Concomitantly, the knockdown of DYRK3 significantly reduces C. neoformans invasion across the HBMEC monolayer in vitro. Our data demonstrate that the lipid raft-dependent endocytosis process mediates C. neoformans internalization into HBMEC and that the CD44 protein of the hosts, cytoskeleton, and intracellular kinase-DYRK3 are involved in this process.Cryptococcus neoformans is the etiologic agent of cryptococcosis, which occurs primarily in immune-compromised hosts and occasionally occurs in normal hosts (1). It is an environmental yeast that initiates infection after inhalation and can disseminate hematogenously to almost every organ. If developed into cryptococcal meningoencephalitis, it is fatal unless treated; and even with treatment the fatality rate is close to 25%. In particular, an infection of the brain and meninges is the most common clinical manifestation of cryptococcosis as well as the most common cause of death from the disease (1, 2). Cryptococcosis becomes one of the most notorious HIV-associated opportunistic infections (3) Annually, close to 1 million cases of cryptococcal meningoencephalitis occur globally, resulting in about 700,000 deaths per year. It is generally accepted that the C. neoformans capsule is the major virulent factor of this pathogen (4).To cause meningoencephalitis, C. neoformans must penetrate through the blood-brain barrier and migrate to the brain cortex. The blood-brain barrier mainly consists of brain microvascular endothelial cells (BMEC) 4 (5). One significant feature of BMEC is their ability to form tight junctions among the endothelial cells. Because of the high density of microvessels inside the brain, it is conceivable that BMEC is the primary site for C. neoformans brain invasion.To determine how C. neoformans invades the brain, we have developed an in vitro blood-brain barrier model to investigate the interaction b...

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Section: Discussionmentioning

confidence: 99%

Invasion of Cryptococcus neoformans into Human Brain Microvascular Endothelial Cells Is Mediated through the Lipid Rafts-Endocytic Pathway via the Dual Specificity Tyrosine Phosphorylation-regulated Kinase 3 (DYRK3)

Huang

Long

et al. 2011

Journal of Biological Chemistry

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“…Finally, infected macrophage cells may travel widely throughout the host circulatory and lymphatic systems, where they interact intimately with one another and with other cell types through transient contacts [12]. We speculate that internalised C. neoformans may use such transient contact in order to cross the blood-brain barrier by direct cell-to-cell spread from adherent infected macrophages to microvascular endothelial cells [14]. In fact, spreading from macrophages to other cell types during dissemination has been demonstrated for other pathogens in vitro .…”

Section: Discussionmentioning

confidence: 99%

Direct cell-to-cell spread of a pathogenic yeast

Croudace

Lammas

et al. 2007

BMC Immunol

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Background: Cryptococcosis, a fatal fungal infection of the central nervous system, is one of the major killers of AIDS patients and other immunocompromised hosts. The causative agent, Cryptococcus neoformans, has a remarkable ability to 'hide' and proliferate within phagocytic cells of the human immune system. This intracellular phase is thought to underlie the ability of the pathogen to remain latent for long periods of time within infected individuals.

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“…Two different studies have found Cr. neoformans cells inside of brain endothelial cells in mice infected intravenously with live organisms [40,41]. Thus, Cr.…”

Section: Cryptococcus Neoformansmentioning

confidence: 99%

“…neoformans with endothelial cells has also been analyzed in vitro. Both encapsulated and unencapsulated organisms are able to induce their own endocytosis by brain microvascular endothelial cells [41,42]. The organisms induce membrane ruffling and projection of microvilli that surround the organisms and pull them into the cell.…”

Section: Cryptococcus Neoformansmentioning

confidence: 99%

Fungal Invasion of Normally Non-Phagocytic Host Cells

Filler¹,

Sheppard²

2006

PLoS Pathog

243

200

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Cryptococcal Yeast Cells Invade the Central Nervous System via Transcellular Penetration of the Blood-Brain Barrier

Abstract: Cryptococcal meningoencephalitis develops as a result of hematogenous dissemination of inhaled

Cited by 237 publications

References 44 publications

Invasion of Cryptococcus neoformans into Human Brain Microvascular Endothelial Cells Is Mediated through the Lipid Rafts-Endocytic Pathway via the Dual Specificity Tyrosine Phosphorylation-regulated Kinase 3 (DYRK3)

Invasion of Cryptococcus neoformans into Human Brain Microvascular Endothelial Cells Is Mediated through the Lipid Rafts-Endocytic Pathway via the Dual Specificity Tyrosine Phosphorylation-regulated Kinase 3 (DYRK3)

Direct cell-to-cell spread of a pathogenic yeast

Fungal Invasion of Normally Non-Phagocytic Host Cells

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