Abstract
Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a prototypical neglected tropical disease. Specific immunity promotes acute phase survival. Nevertheless, one-third of CD patients develop chronic chagasic cardiomyopathy (CCC) associated with parasite persistence and immunological unbalance. Currently, the therapeutic management of patients only mitigates CCC symptoms. Therefore, a vaccine arises as an alternative to stimulate protective immunity and thereby prevent, delay progression and even reverse CCC. We examined this hypothesis by vaccinating mice with replication-defective human Type 5 recombinant adenoviruses (rAd) carrying sequences of amastigote surface protein-2 (rAdASP2) and trans-sialidase (rAdTS) T. cruzi antigens. For prophylactic vaccination, naïve C57BL/6 mice were immunized with rAdASP2+rAdTS (rAdVax) using a homologous prime/boost protocol before challenge with the Colombian strain. For therapeutic vaccination, rAdVax administration was initiated at 120 days post-infection (dpi), when mice were afflicted by CCC. Mice were analyzed for electrical abnormalities, immune response and cardiac parasitism and tissue damage. Prophylactic immunization with rAdVax induced antibodies and H-2Kb-restricted cytotoxic and interferon (IFN)γ-producing CD8+ T-cells, reduced acute heart parasitism and electrical abnormalities in the chronic phase. Therapeutic vaccination increased survival and reduced electrical abnormalities after the prime (analysis at 160 dpi) and the boost (analysis at 180 and 230 dpi). Post-therapy mice exhibited less heart injury and electrical abnormalities compared with pre-therapy mice. rAdVax therapeutic vaccination preserved specific IFNγ-mediated immunity but reduced the response to polyclonal stimuli (anti-CD3 plus anti-CD28), CD107a+ CD8+ T-cell frequency and plasma nitric oxide (NO) levels. Moreover, therapeutic rAdVax reshaped immunity in the heart tissue as reduced the number of perforin+ cells, preserved the number of IFNγ+ cells, increased the expression of IFNγ mRNA but reduced inducible NO synthase mRNA. Vaccine-based immunostimulation with rAd might offer a rational alternative for re-programming the immune response to preserve and, moreover, recover tissue injury in Chagas’ heart disease.
Highlights
Chagas disease (CD) is a neglected tropical illness caused by the protozoan parasite Trypanosoma cruzi, which is transmitted by blood-sucking triatomines
Because of the limited prospect of treatment, vaccine reemerged as a strategy to prevent infection, interfere with CD progression and, reverse heart abnormalities
We showed that prophylactic vaccination reduced heart parasite load, inflammation and electrical abnormalities
Summary
Chagas disease (CD) is a neglected tropical illness caused by the protozoan parasite Trypanosoma cruzi, which is transmitted by blood-sucking triatomines. Despite the successful control of the main vector, an overview of the current challenges reveals the need for (i) permanent vector surveillance and attention to domestic and peri-domestic reservoirs of the parasite, (ii) new strategies to prevent or abrogate infection and (iii) new therapies for patients with chronic forms of CD [2]. Innate and adaptive immunity play pivotal roles in parasite growth control during the acute phase of infection, allowing the establishment of chronic phase [3]. Several studies have proposed veterinary vaccine as tools to prevent infection, to decrease parasitemia in hosts and reservoirs, such as dogs, to control the domestic and peri-domestic cycle [6]. In chronic T. cruzi infections, vaccination should be considered as a therapeutic strategy to redirect immunity to a protective status to delay disease progression and reverse heart alterations in chronic patients
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