Abstract

Defensins play a fundamental role in the initiation of immune responses to selected human pathogens. Here, we show that early cellular infection by T. cruzi up-regulates the expression and secretion of defensin α-1, which displayed a trypanocidal role mediated by pore-formation resulting in apoptosis of the parasite. Analysis of the whole human epithelial cell transcriptome upon short infection of cells by T. cruzi indicates that the parasite up-regulates the levels of transcripts of defensin α-1. Defensin α-1, at concentrations not toxic for host cells, significantly reduced the viability of trypomastigote forms of T. cruzi. Defensin α-1 integrates into the trypanosome membrane to cause pore formation, cellular and mitochondrial membrane depolarization, membrane disorganization and blebbing, DNA fragmentation, and cytoplasmic vacuolization leading to damage and death. Pre-incubation of trypomastigotes with exogenous defensin α-1 followed by exposure to human epithelial cells significantly reduced trypanosome infection. Membrane depolarization of trypanosomes abolished the trypanocidal activity of defensin α-1, indicating that the mechanism of defensin α-1 mediated trypanosome killing is membrane-voltage dependent. We conclude that defensin α-1 gene expression and peptide secretion is an effective host innate immune response to control T. cruzi infection.

(Supported by NIH grants)

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