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Marisa Nia Madison, Yuliya Kleshchenko, Pius Nde, Kaneatra Simmons, Maria F Lima, Fernando Villalta, Defensin α-1 expression is up-regulated in human cells in response to early Trypanosoma cruzi infection as an innate immune mechanism to decrease cellular infection via membrane pore formation leading to apoptosis (51.6), The Journal of Immunology, Volume 178, Issue 1_Supplement, April 2007, Page S97, https://doi.org/10.4049/jimmunol.178.Supp.51.6
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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)