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Identifying novel therapeutic targets for Chagas disease is a scientific priority. Recently, Hossain et al. used an innovative metabolomic approach to define disease tolerance mechanisms and identify therapeutic targets for Chagas disease. This is the first study translating metabolomic data to develop novel treatments for Chagas disease. [ABSTRACT FROM AUTHOR]

• The recombinant multi-epitope Tc24-C4.10E reduces parasitemia peak in acute T. cruzi infected mice. • The recombinant multi-epitope Tc24-C4.10E elicit an antigen-specific CD8 + T cell response producing IFNγ and IL-4 cytokines. • This is the first approach using as scaffold a recombinant protein to fuse 10 CD8 + T. cruzi epitopes. About 6.5 million people worldwide are afflicted by Chagas disease, which is caused by the protozoan parasite Trypanosoma cruzi. The development of a therapeutic vaccine to prevent the progression of Chagasic cardiomyopathy has been proposed as an alternative for antiparasitic chemotherapy. Bioinformatics tools can predict MHC class I CD8 + epitopes for inclusion in a single recombinant protein with the goal to develop a multivalent vaccine. We expressed a novel recombinant protein Tc24-C4.10E harboring ten nonameric CD8 + epitopes and using Tc24-C4 protein as scaffold to evaluate the therapeutic effect in acute T. cruzi infection. T. cruzi -infected mice were immunized with Tc24-C4.10E or Tc24-C4 in a 50-day model of acute infection. Tc24-C4.10E-treated mice showed a decreased parasitemia compared to the Tc24-C4 (non-adjuvant) immunized mice or control group. Moreover, Tc24-C4.10E induced a higher stimulation index of CD8 + T cells producing IFNγ and IL-4 cytokines. These results suggest that the addition of the MHC Class I epitopes to Tc24-C4 can synergize the antigen-specific cellular immune responses, providing proof-of-concept that this approach could lead to the development of a promising vaccine candidate for Chagas disease. [ABSTRACT FROM AUTHOR]

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. Author summary: 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. While animal challenge studies have shown that targeting Tc24 is very promising, it is not fully understood how Tc24 is presented to the immune system. Here, we were able to localize Tc24 in flagellated T. cruzi parasites using a novel Tc24-specific monoclonal antibody. The results showed that Tc24 is not exposed on the outside of the parasite, which suggests that antibodies against Tc24 could not bind parasites during the infection. Then, by analyzing Tc24 expression in T. cruzi—infected host cells over time, we observed that Tc24 expression is reduced after the parasite enters the cells but is restored when parasites escape the host cell again. Our study provides more insights on the location and presence of Tc24 in T. cruzi during infection in the host, and we discuss our current understanding on the mechanisms of how the Tc24 vaccine may work. [ABSTRACT FROM AUTHOR]

Background: Chagas disease (Trypanosoma cruzi infection) is the leading cause of non-ischemic dilated cardiomyopathy in Latin America. Texas, particularly the southern region, has compounding factors that could contribute to T. cruzi transmission; however, epidemiologic studies are lacking. The aim of this study was to ascertain the prevalence of T. cruzi in three different mammalian species (coyotes, stray domestic dogs, and humans) and vectors (Triatoma species) to understand the burden of Chagas disease among sylvatic, peridomestic, and domestic cycles. Methodology/Principal Findings: To determine prevalence of infection, we tested sera from coyotes, stray domestic dogs housed in public shelters, and residents participating in related research studies and found 8%, 3.8%, and 0.36% positive for T. cruzi, respectively. PCR was used to determine the prevalence of T. cruzi DNA in vectors collected in peridomestic locations in the region, with 56.5% testing positive for the parasite, further confirming risk of transmission in the region. Conclusions/Significance: Our findings contribute to the growing body of evidence for autochthonous Chagas disease transmission in south Texas. Considering this region has a population of 1.3 million, and up to 30% of T. cruzi infected individuals developing severe cardiac disease, it is imperative that we identify high risk groups for surveillance and treatment purposes. [ABSTRACT FROM AUTHOR]