EC Accepts, published online ahead of print on 1 May 2009

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Eukaryotic Cell doi:10.1128/EC.00017-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Isolation and characterization of senescent C. neoformans and its implications for phenotypic switching and the pathogenesis of chronic cryptococcosis

Neena Jain, Emily Cook, Immaculata Xess, Fahmi Hasan, Dietrich Fries, and Bettina C. Fries

Departments of Medicine, Microbiology and Immunology of Albert Einstein College of Medicine, Bronx, New York 10461; Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India; Ret. Professor of Physics, Institute für Experimentale Kernphysik, Univ. Karlsruhe, Germany

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. For RC-2, a C. neoformans strain that undergoes phenotypic switching, senescent cells manifest up to 11 fold higher switching rates when compared to 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.