title: A human type 5 adenovirus-based Trypanosoma cruzi therapeutic vaccine re-programs immune response and reverses chronic cardiomyopathy.
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.
authors.affiliation: Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Isabela Resende
authors.initials: IR
authors.lastname: Pereira
authors.affiliation: Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Glaucia
authors.initials: G
authors.lastname: Vilar-Pereira
authors.affiliation: Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Virgínia
authors.initials: V
authors.lastname: Marques
authors.affiliation: Departamento de Patologia, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil.
authors.forename: Andrea Alice
authors.initials: AA
authors.lastname: da Silva
authors.affiliation: Centro de Pesquisas René Rachou, Fiocruz, Belo Horizonte, Minas Gerais, Brazil; Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Vírus Respiratórios e do Sarampo, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Bráulia
authors.initials: B
authors.lastname: Caetano
authors.affiliation: Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Otacilio Cruz
authors.initials: OC
authors.lastname: Moreira
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Alexandre Vieira
authors.initials: AV
authors.lastname: Machado
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, Brazil.
authors.forename: Oscar
authors.initials: O
authors.lastname: Bruna-Romero
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, São Paulo, Brazil.
authors.forename: Maurício Martins
authors.initials: MM
authors.lastname: Rodrigues
authors.affiliation: Centro de Pesquisas René Rachou, Fiocruz, Belo Horizonte, Minas Gerais, Brazil; Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Ricardo Tostes
authors.initials: RT
authors.lastname: Gazzinelli
authors.affiliation: Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Joseli
authors.initials: J
authors.lastname: Lannes-Vieira
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002598:Chagas Cardiomyopathy / Q000517:prevention & control*; D014355:Chagas Disease / Q000276:immunology* / Q000628:therapy*; D002908:Chronic Disease; D005260:Female; D055633:Immune System Phenomena; D051379:Mice; D008810:Mice, Inbred C57BL; D016052:Protozoan Vaccines / Q000627:therapeutic use*; D014349:Trypanosoma cruzi / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology
chemical_list: D016052:Protozoan Vaccines; D019444:Vaccines, DNA