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Infection and Immunity, June 2009, p. 2436-2446, Vol. 77, No. 6
0019-9567/09/$08.00+0     doi:10.1128/IAI.01232-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cryptococcus neoformans Directly Stimulates Perforin Production and Rearms NK Cells for Enhanced Anticryptococcal Microbicidal Activity{triangledown}

Kaleb J. Marr,1 Gareth J. Jones,2 Chunfu Zheng,4 Shaunna M. Huston,1 Martina Timm-McCann,2 Anowara Islam,1 Byron M. Berenger,1 Ling Ling Ma,1 Jeremy C. D. Wiseman,1 and Christopher H. Mody2,3*

Departments of Medical Science,1 Microbiology and Infectious Diseases,2 Internal Medicine, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, Canada,3 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan, China4

Received 9 October 2008/ Returned for modification 21 November 2008/ Accepted 10 March 2009

NK cells, in addition to possessing antitumor and antiviral activity, exhibit perforin-dependent microbicidal activity against the opportunistic pathogen Cryptococcus neoformans. However, the factors controlling this response, particularly whether the pathogen itself provides an activation or rearming signal, are largely unknown. The current studies were performed to determine whether exposure to this fungus alters subsequent NK cell anticryptococcal activity. NK cells lost perforin and mobilized lysosome-associated membrane protein 1 to the cell surface following incubation with the fungus, indicating that degranulation had occurred. Despite a reduced perforin content during killing, NK cells acquired an enhanced ability to kill C. neoformans, as demonstrated using auxotrophs that allowed independent assessment of the killing of two strains. De novo protein synthesis was required for optimal killing; however, there was no evidence that a soluble factor contributed to the enhanced anticryptococcal activity. Exposure of NK cells to C. neoformans caused the cells to rearm, as demonstrated by increased perforin mRNA levels and enhanced loss of perforin when transcription was blocked. Degranulation alone was insufficient to provide the activation signal as NK cells lost anticryptococcal activity following treatment with strontium chloride. However, NK cells regained the activity upon prolonged exposure to C. neoformans, which is consistent with activation by the microbe. The enhanced cytotoxicity did not extend to tumor killing since NK cells exposed to C. neoformans failed to kill NK-sensitive tumor targets (K562 cells). These studies demonstrate that there is contact-mediated microbe-specific rearming and activation of microbicidal activity that are necessary for optimal killing of C. neoformans.

* Corresponding author. Mailing address: Room 4AA14 Health Research Innovation Centre, University of Calgary, Calgary, Alberta, Canada T2N 4N1. Phone: (403) 220-8479. Fax: (403) 210-8463. E-mail: cmody{at}ucalgary.ca

{triangledown} Published ahead of print on 23 March 2009.

Editor: A. Casadevall

Infection and Immunity, June 2009, p. 2436-2446, Vol. 77, No. 6
0019-9567/09/$08.00+0     doi:10.1128/IAI.01232-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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