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Infection and Immunity, January 2009, p. 128-140, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.01079-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Loss of Allergen 1 Confers a Hypervirulent Phenotype That Resembles Mucoid Switch Variants of Cryptococcus neoformans{triangledown} ,{dagger}

Neena Jain,1 Li Li,1 Ye-Ping Hsueh,3 Abraham Guerrero,1 Joseph Heitman,3 David L. Goldman,1,4 and Bettina C. Fries1,2*

Department of Medicine,1 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York,2 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina,3 Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York4

Received 29 August 2008/ Returned for modification 13 October 2008/ Accepted 15 October 2008

Microbial survival in a host is usually dependent on the ability of a pathogen to undergo changes that promote escape from host defense mechanisms. The human-pathogenic fungus Cryptococcus neoformans undergoes phenotypic switching in vivo that promotes persistence in tissue. By microarray and real-time PCR analyses, the allergen 1 gene (ALL1) was found to be downregulated in the hypervirulent mucoid switch variant, both during logarithmic growth and during intracellular growth in macrophages. The ALL1 gene encodes a small cytoplasmic protein that is involved in capsule formation. Growth of an all1{Delta} gene deletion mutant was normal. Similar to cells of the mucoid switch variant, all1{Delta} cells produced a larger polysaccharide capsule than cells of the smooth parent and the complemented strain produced, and the enlarged capsule inhibited macrophage phagocytosis. The mutant exhibited a modest defect in capsule induction compared to all of the other variants. In animal models the phenotype of the all1{Delta} mutant mimicked the hypervirulent phenotype of the mucoid switch variant, which is characterized by decreased host survival and elevated intracranial pressure. Decreased survival is likely the result of both an ineffective cell-mediated immune response and impaired phagocytosis by macrophages. Consequently, we concluded that, unlike loss of most virulence-associated genes, where loss of gene function results in attenuated virulence, loss of the ALL1 gene enhances virulence by altering the host-pathogen interaction and thereby impairing clearance. Our data identified the first cryptococcal gene associated with elevated intracranial pressure and support the hypothesis that an environmental opportunistic pathogen has modified its virulence in vivo by epigenetic downregulation of gene function.

* Corresponding author. Mailing address: Albert Einstein College of Medicine, Ullmann 1223, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: (718) 430-2365. Fax: (718) 430-8968. E-mail: fries{at}aecom.yu.edu

{triangledown} Published ahead of print on 27 October 2008.

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

Editor: W. A. Petri, Jr.

Infection and Immunity, January 2009, p. 128-140, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.01079-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Jain, N., Cook, E., Xess, I., Hasan, F., Fries, D., Fries, B. C. (2009). Isolation and Characterization of Senescent Cryptococcus neoformans and Implications for Phenotypic Switching and Pathogenesis in Chronic Cryptococcosis. Eukaryot Cell 8: 858-866 [Abstract] [Full Text]  


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