Cellular Response to Trypanosoma cruzi Infection Induces Secretion of Defensin α-1, Which Damages the Flagellum, Neutralizes Trypanosome Motility, and Inhibits Infection

Abstract

Human defensins play a fundamental role in the initiation of innate immune responses to some microbial pathogens. Here we show that colonic epithelial model HCT116 cells respond to Trypanosoma cruzi infection by secreting defensin ␣-1, which reduces infection. We also report the early effects of defensin ␣-1 on invasive trypomastigotes that involve damage of the flagellar structure to inhibit parasite motility and reduce cellular infection. Short exposure of defensin ␣-1 to trypomastigotes shows that defensin ␣-1 binds to the flagellum, resulting in flagellar membrane and axoneme alterations, followed by breaking of the flagellar membrane connected to the trypanosome body, leading to detachment and release of the parasite flagellum. In addition, defensin ␣-1 induces a significant reduction in parasite motility in a peptide concentration-dependent manner, which is abrogated by anti-defensin ␣-1 IgG. Preincubation of trypomastigotes with a concentration of defensin ␣-1 that inhibits 50% trypanosome motility significantly reduced cellular infection by 80%. Thus, human defensin ␣-1 is an innate immune molecule that is secreted by HCT116 cells in response to T. cruzi infection, inhibits T. cruzi motility, and plays an important role in reducing cellular infection. This is the first report showing a novel cellular innate immune response to a human parasite by secretion of defensin ␣-1, which neutralizes the motility of a human parasite to reduce cellular infection. The mode of activity of human defensin ␣-1 against T. cruzi and its function may provide insights for the development of new antiparasitic strategies.

Experimental Chagas disease in Balb/c mice previously vaccinated with T. rangeli. II. The innate immune response shows immunological memory: Reality or fiction?

“…Likewise the reduction of NK, F4/80 and Gr-1 cells observed at 24 h post-infection compared to their initial values might account for their marginalization in secondary lymphoid organs or tissues after exercising intense cytotoxic and phagocytic activity. Johnson et al (2013) showed the production of defensins with similar results. This phenomenon was observed previously in our model, in agreement with Arocena et al (2014), in which defensins secreted by Gr-1 cells along with other mediators might be responsible for the parasites' lysis and immobilization.…”

Bovine β-defensin gene family: opportunities to improve animal health?

“…In this regard, it is of interest that increasing the hydrophobicity of a bovine ␤-defensin 123-derived peptide had increased efficacy against MRSA with a 50% lethal dose of 3.91 g/ml in vitro (86). Human ␣-defensins are also effective against trypansomes (72,85), and therefore bovine ␤-defensins could provide novel trypanocidal treatments or breeding targets for one of the most important zoonotic pathogens in the developing world. Murine ␤-defensin-3 has also shown to have potent antiviral effects against influenza virus, both in vitro and in vivo (69).…”

Altering the motility of Trypanosoma cruzi with rabbit polyclonal anti-peptide antibodies reduces infection to susceptible mammalian cells

“…Similarly, invasion to non-phagocytic cells exposed to cytochalasin D, indicate that trypomastigotes can penetrate actively into the cells (Ferreira et al, 2006). Additionally, exposure of trypomastigotes to defensin α-1, resulted in a damaged flagellum without affecting their viability; as a consequence parasite motility was altered and parasite infectivity reduced (Johnson et al, 2013). Whether the mechanism for a decrease in parasite infectivity was a result of energetic depletion was not assessed in this study.…”