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

Yun C. Chang,^1, Monique F. Stins,^2, Michael J. McCaffery,³ Georgina F. Miller,⁴ Dan R. Pare,⁵ Tapen Dam,² Maneesh Paul-Satyasee,² Kwang Sik Kim,² and Kyung J. Kwon-Chung^1*

Molecular Microbiology Section, Laboratory of Clinical Infectious Diseases,¹ Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases,⁵ Division of Veterinary Resources, National Institutes of Health, Bethesda, Maryland,⁴ Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine,² Department of Biology, Johns Hopkins University, Baltimore, Maryland³

Received 16 April 2004/ Returned for modification 20 May 2004/ Accepted 2 June 2004

Cryptococcal meningoencephalitis develops as a result of hematogenous dissemination of inhaled Cryptococcus neoformans from the lung to the brain. The mechanism(s) by which C. neoformans crosses the blood-brain barrier (BBB) is a key unresolved issue in cryptococcosis. We used both an in vivo mouse model and an in vitro model of the human BBB to investigate the cryptococcal association with and traversal of the BBB. Exposure of human brain microvascular endothelial cells (HBMEC) to C. neoformans triggered the formation of microvillus-like membrane protrusions within 15 to 30 min. Yeast cells of C. neoformans adhered to and were internalized by the HBMEC, and they crossed the HBMEC monolayers via a transcellular pathway without affecting the monolayer integrity. The histopathology of mouse brains obtained after intravenous injection of C. neoformans showed that the yeast cells either were associated with endothelial cells or escaped from the brain capillary vessels into the neuropil by 3 h. C. neoformans was found in the brain parenchyma away from the vessels by 22 h. Association of C. neoformans with the choroid plexus, however, was not detected during up to 10 days of observation. Our findings indicate that C. neoformans cells invade the central nervous system by transcellular crossing of the endothelium of the BBB.

Editor: T. R. Kozel

Y.C.C and M.F.S. contributed equally to this work.

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