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Infection and Immunity, September 2008, p. 4322-4331, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.00529-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Phenotypic Switching in Cryptococcus neoformans Contributes to Virulence by Changing the Immunological Host Response{triangledown}

Abraham Guerrero1 and Bettina C. Fries1,2*

Departments of Microbiology and Immunology,1 Medicine, Albert Einstein College of Medicine, Bronx, New York 104612

Received 29 April 2008/ Returned for modification 5 June 2008/ Accepted 12 June 2008

Cryptococcus neoformans is an encapsulated opportunistic organism that can undergo phenotypic switching. In this process, the parent smooth colony (SM) switches to a more virulent mucoid colony (MC) variant. The host responses mounted against the SM and MC variants differ, and lower tissue interleukin 10 (IL-10) levels are consistently observed in lungs of MC-infected C57BL/6 and BALB/c mice. This suggested different roles of this cytokine in SM and MC infections. The objective of this study was to compare survival rates and characterize the host responses of SM- and MC-infected IL-10-depleted (IL-10–/–) mice, which exhibit a Th1-polarized immune response and are considered resistant hosts. As expected, SM-infected IL-10–/– mice survived longer than wild-type mice, whereas MC-infected IL-10–/– mice did not exhibit a survival benefit. Consistent with this observation, we demonstrated marked differences in the inflammatory responses of SM- and MC-infected IL-10–/– and wild-type mice. This included a more Th1-polarized inflammatory response with enhanced recruitment of macrophages and natural killer and CD8 cells in MC- than in SM-infected IL-10–/– and wild-type mice. In contrast, both SM-infected IL-10–/– and wild-type mice exhibited higher recruitment of CD4 cells, consistent with enhanced survival and differences in recruitment and Th1/Th2 polarization. Lung tissue levels of IL-21, IL-6, IL-4, transforming growth factor beta, IL-12, and gamma interferon were higher in MC-infected IL-10–/– and wild-type mice than in SM-infected mice, whereas tumor necrosis factor alpha levels were higher in SM-infected IL-10–/– mice. In conclusion, the MC variant elicits an excessive inflammatory response in a Th1-polarized host environment, and therefore, the outcome is negatively affected by the absence of IL-10.

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

{triangledown} Published ahead of print on 30 June 2008.

Editor: W. A. Petri, Jr.

Infection and Immunity, September 2008, p. 4322-4331, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.00529-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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