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Infection and Immunity, December 2007, p. 5615-5626, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.00530-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Gamma Interferon Confers Resistance to Infection with Staphylococcus aureus in Human Vascular Endothelial Cells by Cooperative Proinflammatory and Enhanced Intrinsic Antibacterial Activities{triangledown}

Henry Beekhuizen* and Joke S. van de Gevel

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

Received 13 April 2007/ Returned for modification 27 June 2007/ Accepted 12 September 2007

Vascular endothelium is an exposed target in systemic endovascular Staphylococcus aureus infections. We reported earlier that the proinflammatory and procoagulant activities of primary human umbilical vein endothelial cells (ECs) after binding and ingestion of S. aureus organisms provide the cells effective means for leukocyte-mediated bacterial elimination. Expanding on this, we now show that these ECs exhibit a modest intrinsic capacity for eliminating intracellular S. aureus that was influenced by cytokines relevant to S. aureus infections. Using various EC infection assays, we showed that gamma interferon (IFN-{gamma}), applied to cultures of ECs prior to or after infection with S. aureus, markedly reduced the level of infection, illustrated by lower percentages of S. aureus-infected ECs and less intracellular bacteria per infected cell. IFN-{gamma}-activated ECs had unaltered abilities to bind S. aureus and processed ingested bacteria by a seemingly conventional phagocytic pathway. IFN-{gamma} treatment rescued EC monolayers from severe injury by virulent clinical S. aureus strains or excessive bacterial numbers. Mechanistically, IFN-{gamma} controls S. aureus infection via IFN-{gamma} receptor, most likely through stimulation of intrinsic endothelial antibacterial mechanisms but independent of processes that deprive bacteria of intracellular L-tryptophan or iron. The antibacterial activity of IFN-{gamma}-stimulated ECs coincided with sustained or slightly elevated endothelial proinflammatory responses that supported monocyte recruitment. In conclusion, we identify IFN-{gamma} as a potent regulatory Th1 cytokine possessing exclusive abilities to augment intrinsic antistaphylocccal effector mechanisms in human ECs without ablating the S. aureus-induced proinflammatory EC responses and, as such, coordinating a protective efficacy of ECs against blood-borne S. aureus infection.

* Corresponding author. Mailing address: Department of Infectious Diseases, C5-38, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. Phone: 31-71-5261784/2613. Fax: 31-71-5266758. E-mail: H.Beekhuizen{at}lumc.nl

{triangledown} Published ahead of print on 24 September 2007.

Editor: J. L. Flynn

Infection and Immunity, December 2007, p. 5615-5626, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.00530-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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