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Eukaryotic Cell, June 2009, p. 858-866, Vol. 8, No. 6
1535-9778/09/$08.00+0     doi:10.1128/EC.00017-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Isolation and Characterization of Senescent Cryptococcus neoformans and Implications for Phenotypic Switching and Pathogenesis in Chronic Cryptococcosis{triangledown}

Neena Jain,1 Emily Cook,1 Immaculata Xess,2 Fahmi Hasan,2 Dietrich Fries,3 and Bettina C. Fries1*

Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461,1 Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India,2 Institute für Experimentale Kernphysik, Universität Karlsruhe, Karlsruhe, Germany3

Received 12 January 2009/ Accepted 17 April 2009

Although several virulence factors and associated genes have been identified, the mechanisms that allow Cryptococcus neoformans to adapt during chronic infection and to persist in immunocompromised hosts remain poorly understood. Characterization of senescent cells of C. neoformans demonstrated that these cells exhibit a significantly enlarged cell body and capsule but still cross the blood-brain barrier. C. neoformans cells with advanced generational age are also more resistant to phagocytosis and killing by antifungals, which could promote their selection during chronic disease in humans. Senescent cells of RC-2, a C. neoformans strain that undergoes phenotypic switching, manifest switching rates up to 11-fold higher than those of younger cells. Infection experiments with labeled cells suggest that senescent yeast cells can potentially accumulate in vivo. Mathematical modeling incorporating different switching rates demonstrates how increased switching rates promote the emergence of hypervirulent mucoid variants during chronic infection. Our findings introduce the intriguing concept that senescence in eukaryotic pathogens could be a mechanism of microevolution that may promote pathoadaptation and facilitate evasion of an evolving immune response.

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

{triangledown} Published ahead of print on 1 May 2009.

Eukaryotic Cell, June 2009, p. 858-866, Vol. 8, No. 6
1535-9778/09/$08.00+0     doi:10.1128/EC.00017-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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