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Urease Expression by Cryptococcus neoformans Promotes Microvascular Sequestration, Thereby Enhancing Central Nervous System Invasion

https://doi.org/10.1016/S0002-9440(10)63734-0Get rights and content

Our objective was to determine the role of the cryptococcal virulence factor urease in pulmonary-to-central nervous system, dissemination, invasion, and growth. C. neoformans H99, the urease knockout strain (ure1) derived from H99, and the urease restored strain ure1+URE1−1 were used for thestudies. The absence of cryptococcal urease (ure1infection) resulted in significant protection from the high mortality observed in H99-infected mice. All H99-infected mice had extremely high cryptococcal loads in their brains at the time of death, whereas only two of six animals that died of ure1 infection had detectable C. neoformans in the brain. Histological analysis of the blood-to-brain invasion by C. neoformans H99 demonstrated wedging of the yeasts in small capillaries, altered structure of microvessel walls, formation of mucoid cysts initiated in the proximity of damaged microcapillaries, and the absence of an inflammatory response. Direct inoculation of H99, ure1, and ure1+URE1−1 into the brain demonstrated that urease was not required to grow in the brain. However, the dissemination patterns in the brain, spleen, and other organs after intravenous inoculation indicated that cryptococcal urease contributes to the central nervous system invasion by enhancing yeast sequestration within microcapillary beds (such as within the brain) during hematogenous spread, thereby facilitating blood-to-brain invasion by C. neoformans.

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Supported by the Veteran's Administration (merit grants to M.A.O. and G.B.T., Research Enhancement Award Program grant to G.B.T. and M.A.O.), the National Institutes of Health (NHLBI R01-HL63670 to G.B.H., NHLBI R01-HL65912 to G.B.H., NHLBI R01-HL51082 to G.B.T., NHLBI T32-HL07749 to G.B.H. and M.A.O., and RO1-AI28388 to J.R.P.), and the Burroughs-Wellcome Fund (to G.B.H.).

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