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Infection and Immunity, August 2009, p. 3450-3457, Vol. 77, No. 8
0019-9567/09/$08.00+0     doi:10.1128/IAI.00297-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cytokine Signaling Regulates the Outcome of Intracellular Macrophage Parasitism by Cryptococcus neoformans{triangledown}

Kerstin Voelz,1 David A. Lammas,2 and Robin C. May1*

School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom,1 Division of Immunity and Infection, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom2

Received 16 March 2009/ Returned for modification 12 May 2009/ Accepted 23 May 2009

The pathogenic yeast Cryptococcus neoformans and C. gattii commonly cause severe infections of the central nervous system in patients with impaired immunity but also increasingly in immunocompetent individuals. Cryptococcus is phagocytosed by macrophages but can then survive and proliferate within the phagosomes of these infected host cells. Moreover, Cryptococcus is able to escape into the extracellular environment via a recently discovered nonlytic mechanism (termed expulsion or extrusion). Although it is well established that the host's cytokine profile dramatically affects the outcome of cryptococcal disease, the molecular basis for this effect is unclear. Here, we report a systematic analysis of the influence of Th1, Th2, and Th17 cytokines on the outcome of the interaction between macrophages and cryptococci. We show that Th1 and Th17 cytokines activate, whereas Th2 cytokines inhibit, anticryptococcal functions. Intracellular yeast proliferation and cryptococcal expulsion rates were significantly lower after treatment with the Th1 cytokines gamma interferon and tumor necrosis factor alpha and the Th17 cytokine interleukin-17 (IL-17). Interestingly, however, the Th2 cytokines IL-4 and IL-13 significantly increased intracellular yeast proliferation while reducing the occurrence of pathogen expulsion. These results help explain the observed poor prognosis associated with the Th2 cytokine profile (e.g., in human immunodeficiency virus-infected patients).

* Corresponding author. Mailing address: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. Phone: 44 (0) 121 41 45418. Fax: 44 (0) 121 41 45925. E-mail: R.C.May{at}bham.ac.uk

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

Editor: A. Casadevall

Infection and Immunity, August 2009, p. 3450-3457, Vol. 77, No. 8
0019-9567/09/$08.00+0     doi:10.1128/IAI.00297-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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