Abstract
Tc24-C4, a modified recombinant flagellar calcium-binding protein of Trypanosoma cruzi, is under development as a therapeutic subunit vaccine candidate to prevent or delay progression of chronic Chagasic cardiomyopathy. When combined with Toll-like receptor agonists, Tc24-C4 immunization reduces parasitemia, parasites in cardiac tissue, and cardiac fibrosis and inflammation in animal models. To support further research on the vaccine candidate and its mechanism of action, murine monoclonal antibodies (mAbs) against Tc24-C4 were generated. Here, we report new findings made with mAb Tc24-C4/884 that detects Tc24-WT and Tc24-C4, as well as native Tc24 in T. cruzi on ELISA, western blots, and different imaging techniques. Surprisingly, detection of Tc24 by Tc24-C/884 in fixed T. cruzi trypomastigotes required permeabilization of the parasite, revealing that Tc24 is not exposed on the surface of T. cruzi, making a direct role of antibodies in the induced protection after Tc24-C4 immunization less likely. We further observed that after immunostaining T. cruzi-infected cells with mAb Tc24-C4/884, the expression of Tc24 decreases significantly when T. cruzi trypomastigotes enter host cells and transform into amastigotes. However, Tc24 is then upregulated in association with parasite flagellar growth linked to re-transformation into the trypomastigote form, prior to host cellular escape. These observations are discussed in the context of potential mechanisms of vaccine immunity.
Highlights
Chagas disease is a neglected tropical disease caused by the protozoan Trypanosoma cruzi
Chagas disease is a chronic infection with Trypanosoma cruzi (T. cruzi) that affects approximately 8 million people worldwide and may cause chronic heart inflammation
The vaccine candidate Tc24-C4 is a recombinant version of the Tc24 protein, which is a flagellar calcium-binding protein expressed by T. cruzi
Summary
Chagas disease is a neglected tropical disease caused by the protozoan Trypanosoma cruzi. [1] From individuals who become chronically infected with the disease, 30–40% develop cardiomyopathy, arrhythmias, and megaviscera.[2] There are only two anti-trypanosomal drugs, nifurtimox and benznidazole, which are licensed to treat Chagas disease. Because both drugs have severe adverse side effects and exhibit low efficacy in the chronic phase of infection, there is an urgent need for alternative, complementary or more effective treatments.[3,4] Prophylactic and therapeutic vaccines are considered potential immune strategies to control T. cruzi infection and/or progression of disease.[5]. A suitable platform was developed for the large scale production of recombinant Tc24 [13] and Tc24 was selected as one of the key antigens under consideration for a human therapeutic Chagas disease vaccine[14] supported by multiple preclinical studies with a recombinant Tc24 vaccine. [12,15,16]
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