Abstract
The development of new adjuvants enables fine modulation of the elicited immune responses. Ideally, the use of one or more adjuvants should result in the induction of a protective immune response against the specific pathogen. We have evaluated the immune response and protection against Trypanosoma cruzi infection in mice vaccinated with recombinant Tc52 or its N- and C-terminal domains (NTc52 and CTc52) adjuvanted either with the STING (Stimulator of Interferon Genes) agonist cyclic di-AMP (c-di-AMP), a pegylated derivative of α-galactosylceramide (αGC-PEG), or oligodeoxynucleotides containing unmethylated CpG motifs (ODN-CpG). All groups immunized with the recombinant proteins plus adjuvant: Tc52+c-di-AMP, NTc52+c-di-AMP, CTc52+c-di-AMP, NTc52+c-di-AMP+αGC-PEG, NTc52+CpG, developed significantly higher anti-Tc52 IgG titers than controls. Groups immunized with c-di-AMP and Tc52, NTc52 or CTc52 showed the highest Tc52-specific IgA titers in nasal lavages. All groups immunized with the recombinant proteins plus adjuvant developed a strong specific cellular immune response in splenocytes and lymph node cells with significant differences for groups immunized with c-di-AMP and Tc52, NTc52 or CTc52. These groups also showed high levels of Tc52-specific IL-17 and IFN-γ producing cells, while NTc52+CpG group only showed significant difference with control in IFN-γ producing cells. Groups immunized with c-di-AMP and Tc52, NTc52 or CTc52 developed predominantly a Th17 and Th1immune response, whereas for NTc52+CpG it was a dominant Th1 response. It was previously described that αGC-PEG inhibits Th17 differentiation by activating NKT cells. Thus, in this work we have also included a group immunized with both adjuvants (NTc52+c-di-AMP+αGC-PEG) with the aim to modulate the Th17 response induced by c-di-AMP. This group showed a significant reduction in the number of Tc52-specific IL-17 producing splenocytes, as compared to the group NTc52+c-di-AMP, which has in turn correlated with a reduction in protection against infection. These results suggest that the Th17 immune response developed after immunizing with NTc52+c-di-AMP could have a protective role against T. cruzi infection. Groups NTc52+c-di-AMP, Tc52+c-di-AMP and NTc52PB, were the ones that showed better protection against infection with lower parasitemia and weight loss, and higher survival.
Highlights
Recent estimations indicate that about 6–7 million people are infected worldwide with Trypanosoma cruzi [1], a protozoan parasite that is the etiological agent of Chagas disease [2]
The infection in humans has an initial acute stage followed by a chronic stage where up to 30% of patients develop cardiac alterations and 10% develop digestive, neurological or mixed alterations
This research provides information about the immune response and protection against Trypanosoma cruzi infection elicited by Tc52 or portions of this molecule using different adjuvants
Summary
Recent estimations indicate that about 6–7 million people are infected worldwide with Trypanosoma cruzi [1], a protozoan parasite that is the etiological agent of Chagas disease [2]. Geographic distribution of Chagas disease spread in the last decades due to migration, with more than 300,000 people being infected in the United States, as indicated by CDC estimations [4]. T. cruzi new infections in North America, Europe and Asia are mainly the consequence of transfusion of contaminated blood, congenital transmission and organ transplantation. Only two drugs are used for treatment: Nifurtimox and Benznidazole Both are effective in the acute stage of infection, lose effectiveness in the advanced phase, and have important side effects associated to the treatment [5, 6]. Efforts are focused in transmission control and the search for more efficient and less toxic drugs, and in the development of prophylactic and therapeutic vaccines
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