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Rapid conditional targeted ablation of cells expressing human CD59 in transgenic mice by intermedilysin

Nature Medicine volume 14, pages 98–103 (2008)Cite this article

Abstract

Conditional targeted cell ablation is a powerful approach for investigating the pathogenesis of human diseases and in vivo cellular functions. Intermedilysin (ILY) is a cytolytic pore-forming toxin secreted by Streptococcus intermedius that lyses human cells exclusively, owing to its receptor specificity for human CD59. We generated two transgenic mouse strains that express human CD59 either on erythrocytes (strain ThCD59RBC) or on endothelia (strain ThCD59END). Intravenous injection of ILY in ThCD59RBC mice induced acute intravascular hemolysis, leading to reduced nitric oxide bioavailability, increased platelet activation and rapid death. In ThCD59END mice, ILY induced rapid endothelial damage, leading to acute death and disseminated intravascular coagulation. Additionally, we show that human serum contains ILY-specific neutralizing antibodies not found in any other animal species. Together, these results suggest that this new rapid conditional targeted ILY-mediated cell ablation technique can be used in combination with any available transgenic expression system to study the physiologic role of specific cell populations.

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Figure 1: Conditional and specific erythrocyte cell ablation in ThCD59RBC mice.
Figure 2: Human serum contains ILY-neutralizing antibodies, but sera from other species do not.
Figure 3: Validation of the animal model.
Figure 4: Conditional and targeted endothelial ablation in ThCD59END mice.
Figure 5: The sequelae of rapid endothelial ablation in ThCD59END mice.

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Acknowledgements

This work was supported by US National Institutes of Health grants RO1 DK060979 (J.A.H.) and RO1 AI061174 (X.Q.) and by a Scientist Development grant from the American Heart Association (0435483N; X.Q.). We are grateful to G.W. Byrne for providing the vector that contains the hemoglobin promoter and a locus control region, to P.J. Cowan for providing the vector that contains the ICAM-2 promoter, to M. Fan for comments, to G. Kunos for critical reading of the manuscript and to the Brigham and Women's Hospital Editorial Service for editorial assistance.

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Authors and Affiliations

  1. Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, 02115, Massachusetts, USA

    Weiguo Hu, Jose A Halperin & Xuebin Qin

  2. Harvard Medical School, Laboratory for Translational Research, One Kendall Square, Building 600, Third Floor, Cambridge, 02139, Massachusetts, USA

    Weiguo Hu, Sean P Ferris, Gongxiong Wu, Jose A Halperin & Xuebin Qin

  3. Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, Oklahoma, USA

    Rodney K Tweten

  4. Division of Metabolism and Health Effects, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Svetlana Radaeva

  5. Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Bin Gao

  6. Rodent Histopathology Core, Dana Farber/Harvard Cancer Center, Boston, 02115, Massachusetts, USA

    Roderick T Bronson

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  1. Weiguo Hu
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Hu, W., Ferris, S., Tweten, R. et al. Rapid conditional targeted ablation of cells expressing human CD59 in transgenic mice by intermedilysin. Nat Med 14, 98–103 (2008). https://doi.org/10.1038/nm1674

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