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Infection and Immunity, August 2005, p. 4922-4933, Vol. 73, No. 8
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.8.4922-4933.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cryptococcus neoformans {alpha} Strains Preferentially Disseminate to the Central Nervous System during Coinfection

Kirsten Nielsen,1,6 Gary M. Cox,1,3 Anastasia P. Litvintseva,1 Eleftherios Mylonakis,9 Stephanie D. Malliaris,7,8 Daniel K. Benjamin Jr.,4 Steven S. Giles,2,3 Thomas G. Mitchell,1 Arturo Casadevall,7,8 John R. Perfect,3 and Joseph Heitman1,3,5,6*

Departments of Molecular Genetics and Microbiology,1 Cell Biology,2 Medicine,3 Pediatrics,4 Pharmacology and Cancer Biology,5 Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710,6 Divisions of Infectious Diseases,7 Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461,8 Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts 021149

Received 14 February 2005/ Returned for modification 7 March 2005/ Accepted 15 March 2005

Cryptococcus neoformans is a fungal pathogen that has evolved over the past 40 million years into three distinct varieties or sibling species (gattii, grubii, and neoformans). Each variety manifests differences in epidemiology and disease, and var. grubii strains are responsible for the vast majority of human disease. In previous studies, {alpha} strains were more virulent than congenic a strains in var. neoformans, whereas var. grubii congenic a and {alpha} strains exhibited equivalent levels of virulence. Here the role of mating type in the virulence of var. grubii was further characterized in a panel of model systems. Congenic var. grubii a and {alpha} strains had equivalent survival rates when cultured with amoebae, nematodes, and macrophages. No difference in virulence was observed between a and {alpha} congenic strains in multiple inbred-mouse genetic backgrounds, and there was no difference in accumulations in the central nervous system (CNS) late in infection. In contrast, during coinfections, a and {alpha} strains are equivalent in peripheral tissues but {alpha} cells have an enhanced predilection to penetrate the CNS. These studies reveal the first virulence difference between congenic a and {alpha} strains in the most common pathogenic variety and suggest an explanation for the prevalence of {alpha} strains in clinical isolates.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, 322 CARL Building, Research Drive, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-2824. Fax: (919) 684-5458. E-mail: heitm001{at}duke.edu.

Editor: T. R. Kozel

Infection and Immunity, August 2005, p. 4922-4933, Vol. 73, No. 8
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.8.4922-4933.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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