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

Natacha Cerny,Silvia Inés Cazorla,Andrés Sanchez Alberti,Augusto Ernesto Bivona,Emilio Luis Malchiodi,Sebastián Nicolás Trinitario,Alejandro Cardoso Landaburu,Celina Morales

doi:10.3389/fimmu.2020.565142

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.

Highlights

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, due to migration, into several other countries [1, 2]
After the promising results observed upon the administration of the therapeutic vaccines during the acute phase, conducted using the acute model described in Figure 2A, we evaluated the performance of the vaccines when administered during the chronic phase of the infection (Figure 6A)
Millions of people are waiting for a development of anti-T. cruzi vaccines for prophylactic and therapeutic purposes to stop Chagas disease progression

Summary

Introduction

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, due to migration, into several other countries [1, 2]. Despite vector control programs effectively reducing the level of infestation, when they are not sustained over time, reinfection of treated households reaches levels like the initial one [6]. This was mainly seen in rural areas, when constructions are poor or in peridomestic areas with domestic animals [7]. Several concerns remain a challenge, namely, disease globalization due to migration [1, 8]; the existence of alternative routes of transmission, such as mother-to-child or oral transmission through contaminated food or beverages [9]; and the high variability in drug sensitivity across multiple strains of T. cruzi [10]

Methods

Results

Conclusion