Cruzipain and Its Physiological Inhibitor, Chagasin, as a DNA-Based Therapeutic Vaccine Against Trypanosoma cruzi

Abstract

Chagas disease caused by the protozoan parasite Trypanosoma cruzi is endemic in 21 Latin American countries and the southern United States and now is spreading into several other countries due to migration. Despite the efforts to control the vector throughout the Americas, currently, there are almost seven million infected people worldwide, causing ~10,000 deaths per year, and 70 million people at risk to acquire the infection. Chagas disease treatment is restricted only to two parasiticidal drugs, benznidazole and nifurtimox, which are effective during the acute and early infections but have not been found to be as effective in chronic infection. No prophylactic or therapeutic vaccine for human use has been communicated at this moment. Here, we evaluate in a mouse model a therapeutic DNA vaccine combining Cruzipain (Cz), a T. cruzi cysteine protease that proved to be protective in several settings, and Chagasin (Chg), which is the natural Cz inhibitor. The DNAs of both antigens, as well as a plasmid encoding GM-CSF as adjuvant, were orally administrated and delivered by an attenuated Salmonella strain to treat mice during the acute phase of T. cruzi infection. The bicomponent vaccine based on Salmonella carrying Cz and Chg (SChg+SCz) was able to improve the protection obtained by each antigen as monocomponent therapeutic vaccine and significantly increased the titers of antigen- and parasite-specific antibodies. More importantly, the bicomponent vaccine triggered a robust cellular response with interferon gamma (IFN-γ) secretion that rapidly reduced the parasitemia during the acute phase and decreased the tissue damage in the chronic stage of the infection, suggesting it could be an effective tool to ameliorate the pathology associated to Chagas disease.

Vaccination with parasite-specific TcTASV proteins combined with recombinant baculovirus as a delivery platform protects against acute and chronic Trypanosoma cruzi infection

“…Several vaccines against T. cruzi have been pre-clinically tested in animal models, using different antigens and platforms. Most assayed antigens are well-characterized parasite virulence factors belonging to large multigene families, such as trans -sialidase, ASP-2, and cruzipain ( Tzelepis et al., 2008 ; Haolla et al., 2009 ; Bontempi et al., 2015 , 2017 ; Cerny et al., 2020 ; Moraschi et al., 2021 ; Castro et al., 2023 ; Jha et al., 2023 ). However, to date, none antigen-defined vaccines have been able to induce an immune response that avoids an initial infection with the parasite.…”

Immunization with a recombinant ASP-2/Transialidase chimeric protein induces robust protective immunity in both murine and canine models of Chagas’ disease

“…Among these vaccine candidates different groups have used the TS, ASP-2, Tc24, cruzipain, members of TcG family and other antigens [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][60][61][62][63][64][65][66][67]. For a complete list, please see reviews by Malchiodi [68] and Garg [10].…”

In Vitro, In Vivo, and In Silico Studies of Cumanin Diacetate as a Potential Drug against Trypanosoma cruzi Infection

“…There is a special interest in compounds that target the amastigote stage, particularly drugs that are active against the slow or nonproliferating forms of amastigotes as dormancy may play a key role in sterile cure. 30 In this sense, determination of its effect on dormant amastigotes as well as its combination with benznidazole or new vaccines as immunotherapies 31,32 will be an aspect of future research. The efficacy of cumanin diacetate in the T. cruzi K98 BALB/c infection model is in accordance with others reported for STLs 33−36 reinforcing the utility of this group of compounds in vivo.…”