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Infection and Immunity, October 2007, p. 4780-4791, Vol. 75, No. 10
0019-9567/07/$08.00+0     doi:10.1128/IAI.00557-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Human Defensin {alpha}-1 Causes Trypanosoma cruzi Membrane Pore Formation and Induces DNA Fragmentation, Which Leads to Trypanosome Destruction{triangledown}

M. Nia Madison,{dagger} Yuliya Y. Kleshchenko,{dagger} Pius N. Nde, Kaneatra J. Simmons, Maria F. Lima, and Fernando Villalta*

Department of Microbial Pathogenesis and Immune Response, School of Medicine, Meharry Medical College, Nashville, Tennessee 37208

Received 17 April 2007/ Returned for modification 20 May 2007/ Accepted 9 July 2007

Human defensins play a fundamental role in the initiation of innate immune responses to some microbial pathogens. Here we show that human defensin {alpha}-1 displays a trypanocidal role against Trypanosoma cruzi, the causative agent of Chagas' disease. The toxicity of human defensin {alpha}-1 against T. cruzi is mediated by membrane pore formation and the induction of nuclear and mitochondrial DNA fragmentation, leading to trypanosome destruction. Exposure of trypomastigote and amastigote forms of T. cruzi to defensin {alpha}-1 significantly reduced parasite viability in a peptide concentration-dependent and saturable manner. The toxicity of defensin {alpha}-1 against T. cruzi is blocked by anti-defensin {alpha}-1 immunoglobulin G. Electron microscopic analysis of trypomastigotes exposed to defensin {alpha}-1 revealed pore formation in the cellular and flagellar membranes, membrane disorganization, and blebbing as well as cytoplasmic vacuolization. Furthermore, human defensin {alpha}-1 enters the trypanosome when membrane pores are present and is associated with later intracellular damage. Trypanosome membrane depolarization abolished the toxicity of defensin {alpha}-1 against the parasite. Preincubation of trypomastigotes with defensin {alpha}-1 followed by exposure to human epithelial cells significantly reduced T. cruzi infection in these cells. Thus, human defensin {alpha}-1 is an innate immune molecule that causes severe toxicity to T. cruzi and plays an important role in reducing cellular infection. This is the first report showing that human defensin {alpha}-1 causes membrane pore formation in a human parasite, leading to trypanosome destruction.

* Corresponding author. Mailing address: Department of Microbial Pathogenesis and Immune Response, School of Medicine, Meharry Medical College, 1005 Dr. D. B. Todd Jr. Blvd., Nashville, TN 37208. Phone: (615) 327-6667. Fax: (615) 327-6072. E-mail: fvillalta{at}mmc.edu

{triangledown} Published ahead of print on 16 July 2007.

Editor: W. A. Petri, Jr.

{dagger} M.N.M. and Y.Y.K. contributed equally to this work.

Infection and Immunity, October 2007, p. 4780-4791, Vol. 75, No. 10
0019-9567/07/$08.00+0     doi:10.1128/IAI.00557-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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