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Infection and Immunity, January 2009, p. 120-127, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.01065-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Evidence of a Role for Monocytes in Dissemination and Brain Invasion by Cryptococcus neoformans ^,

Caroline Charlier,¹ Kirsten Nielsen,² Samira Daou,¹ Madly Brigitte,³ Fabrice Chretien,³ and Françoise Dromer^1*

Institut Pasteur, Unité de Mycologie Moléculaire, CNRS URA3012, Paris, France,¹ Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455,² INSERM U841, IMRB, Team 10, and Département de Pathologie, Hôpital Henri Mondor, APHP, Université Paris 12, Val-de-Marne, Créteil F-94000, France³

Received 27 August 2008/ Returned for modification 11 September 2008/ Accepted 8 October 2008

The pathogenesis of cryptococcosis, including the events leading to the production of meningoencephalitis, is still largely unknown. Evidence of a transcellular passage of Cryptococcus neoformans across the blood-brain barrier (BBB) and subsequent BBB disruption exists, but the paracellular passage of free yeasts and the role of monocytes in yeast dissemination and brain invasion (Trojan horse method) remain uncertain. We used our model of disseminated cryptococcosis, in which crossing of the BBB starts 6 h after intravenous inoculation, to study paracellular passage of the BBB. We prepared bone marrow-derived monocytes (BMDM) infected in vitro with C. neoformans (BMDM yeasts) and free yeasts and measured fungal loads in tissues. (i) Spleen and lung CFU were >2-fold higher in mice treated with BMDM yeasts than in those treated with free yeasts for 1 and 24 h (P < 0.05), while brain CFU were increased (3.9 times) only at 24 h (P < 0.05). (ii) By comparing the kinetics of brain invasion in naïve mice and in mice with preestablished cryptococcosis, we found that CFU were lower in the latter case, except at 6 h, when CFU from mice inoculated with BMDM yeasts were comparable to those measured in naïve mice and 2.5-fold higher than those in mice with preestablished cryptococcosis who were inoculated with free yeasts. (iii) Late phagocyte depletion obtained by clodronate injection reduced disease severity and lowered the fungal burden by 40% in all organs studied. These results provide evidence for Trojan horse crossing of the BBB by C. neoformans, together with mechanisms involving free yeasts, and overall for a role of phagocytes in fungal dissemination.

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* Corresponding author. Mailing address: Unité de Mycologie Moléculaire, CNRS URA3012, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France. Phone: 33 1 40 61 33 89. Fax: 33 1 45 68 84 20. E-mail: francoise.dromer{at}pasteur.fr

Published ahead of print on 20 October 2008.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: A. Casadevall

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Infection and Immunity, January 2009, p. 120-127, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.01065-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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