New mechanism of innate immunity mediated by human defensin α-1 against Trypanosoma cruzi (37.2)

Abstract

Abstract The mechanisms of innate immunity against protozoan parasites that cause significant diseases are very limited. Here we show that human defensin α-1 plays a fundamental role in the initiation of innate immune responses to Trypanosoma cruzi. We demonstrate that human epithelial cells respond to early T. cruzi infection by up-regulating the expression and secretion of defensin α-1, which inhibits T. cruzi motility and prevents cellular infection. Human defensin α-1 inhibits trypomastigote motility of T. cruzi and infection at low micromolar concentrations, and this requires direct association of the defensin α-1 with the invasive trypanosome, which causes membrane depolarization and pore formation in the flagellar membrane. Moreover, defensin α-1 alters the flagellar axonemes, breaks both the flagellar membrane that attaches the flagellum to the trypanosome body and the flagellum thereby restricting trypanosome motility, which is required for trypanosome membrane penetration during cell entry. This is the first report showing that defensin α-1 disrupts the T. cruzi flagellum to compromise trypanosome motility and prevents cellular infection. Thus, defensin α-1 possess remarkably distinct modes of activity against protozoan parasites than bacteria and viruses, and their function may provide insights for the development of new antitrypanosomal strategies (supported by NIH grants AI AI080580 and AI007281)