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Infection and Immunity, December 2008, p. 5729-5737, Vol. 76, No. 12
0019-9567/08/$08.00+0     doi:10.1128/IAI.00896-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Cryptococcus neoformans Rho-GDP Dissociation Inhibitor Mediates Intracellular Survival and Virulence{triangledown}

Michael S. Price,1,2 Connie B. Nichols,2 and J. Andrew Alspaugh1,2*

Department of Molecular Genetics and Microbiology,1 Department of Medicine, Duke University Medical Center, Durham, North Carolina 277102

Received 21 July 2008/ Returned for modification 26 August 2008/ Accepted 30 August 2008

Rho-GDP dissociation inhibitors (Rho-GDI) are repressors of Rho-type monomeric GTPases that control fundamental cellular processes, such as cytoskeletal arrangement, vesicle trafficking, and polarized growth. We identified and altered the expression of the gene encoding a Rho-GDI homolog in the human fungal pathogen Cryptococcus neoformans and investigated its impact on pathogenicity in animal models of cryptococcosis. Consistent with its predicted function to inhibit and sequester Rho-type GTPases, overexpression of RDI1 results in cytosolic localization of Cdc42. Likely as a result of this finding, RDI1-overexpressing strains exhibited altered morphology compared to that of the wild type, with apparent defects in maintaining proper cell polarity and cytokinesis. RDI1 deletion resulted in increased vacuole size in tissue culture medium and aberrant cell morphology at neutral pH. Maintenance of normal cell morphology is vital for C. neoformans pathogenicity. Accordingly, the rdi1{Delta} mutant strain also showed reduced intracellular survival in macrophages and severe attenuation of virulence in two murine models of cryptococcosis. This reduction in virulence of the rdi1{Delta} mutant occurs in the absence of major growth defects in rich medium and with classical virulence-associated phenotypes.

* Corresponding author. Mailing address: Department of Medicine, Duke University Medical Center, DUMC 3355, Durham, NC 27710. Phone: (919) 684-5054. Fax: (919) 684-8902. E-mail: andrew.alspaugh{at}duke.edu

{triangledown} Published ahead of print on 8 September 2008.

Editor: A. Casadevall

Infection and Immunity, December 2008, p. 5729-5737, Vol. 76, No. 12
0019-9567/08/$08.00+0     doi:10.1128/IAI.00896-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Orlando, K., Guo, W. (2009). Membrane Organization and Dynamics in Cell Polarity. Cold Spring Harb. Perspect. Biol. 1: a001321-a001321 [Abstract] [Full Text]  
  • Nichols, C. B., Ferreyra, J., Ballou, E. R., Alspaugh, J. A. (2009). Subcellular Localization Directs Signaling Specificity of the Cryptococcus neoformans Ras1 Protein. Eukaryot Cell 8: 181-189 [Abstract] [Full Text]  


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