Efficacy of an Immunotherapy Combining Immunogenic Chimeric Protein Plus Adjuvant and Amphotericin B against Murine Visceral Leishmaniasis

Author:

Vale Danniele L.1,Freitas Camila S.1ORCID,Martins Vívian T.1,Moreira Gabriel J. L.2,Machado Amanda S.1,Ramos Fernanda F.1ORCID,Pereira Isabela A. G.1,Bandeira Raquel S.1,de Jesus Marcelo M.1,Tavares Grasiele S. V.1,Ludolf Fernanda1,Chávez-Fumagalli Miguel A.3ORCID,Galdino Alexsandro S.4ORCID,Fujiwara Ricardo T.5ORCID,Bueno Lílian L.5,Roatt Bruno M.2,Christodoulides Myron6ORCID,Coelho Eduardo A. F.17ORCID,Lage Daniela P.1

Affiliation:

1. Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil

2. Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas/NUPEB, Departamento de Ciências Biológicas, Insituto de Ciências Exatas e Biológicas, Universidade Federal de Ouro Preto, Ouro Preto 35400-000, Minas Gerais, Brazil

3. Computational Biology and Chemistry Research Group, Vicerrectorado de Investigación, Universidad Católica de Santa María, Urb. San José S/N, Umacollo, Arequipa 04000, Peru

4. Laboratório de Biotecnologia de Microrganismos, Universidade Federal de São João Del-Rei, Divinópolis 35501-296, Minas Gerais, Brazil

5. Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil

6. Neisseria Research Group, Molecular Microbiology, School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton SO16 6YD, UK

7. Departamento de Patologia Clínica, Colégio Técnico (COLTEC), Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Belo Horizonte 31270-901, Minas Gerais, Brazil

Abstract

Visceral leishmaniasis (VL) in the Americas is a chronic systemic disease caused by infection with Leishmania infantum parasites. The toxicity of antileishmanial drugs, long treatment course and limited efficacy are significant concerns that hamper adequate treatment against the disease. Studies have shown the promise of an immunotherapeutics approach, combining antileishmanial drugs to reduce the parasitism and vaccine immunogens to activate the host immune system. In the current study, we developed an immunotherapy using a recombinant T cell epitope-based chimeric protein, ChimT, previously shown to be protective against Leishmania infantum, with the adjuvant monophosphoryl lipid A (MPLA) and amphotericin B (AmpB) as the antileishmanial drug. BALB/c mice were infected with L. infantum stationary promastigotes and later they received saline or were treated with AmpB, MPLA, ChimT/Amp, ChimT/MPLA or ChimT/MPLA/AmpB. The combination of ChimT/MPLA/AmpB significantly reduced the parasite load in mouse organs (p < 0.05) and induced a Th1-type immune response, which was characterized by higher ratios of anti-ChimT and anti-parasite IgG2a:IgG1 antibodies, increased IFN-γ mRNA and IFN-γ and IL-12 cytokines and accompanied by lower levels of IL-4 and IL-10 cytokines, when compared to other treatments and controls (all p < 0.05). Organ toxicity was also lower with the ChimT/MPLA/AmpB immunotherapy, suggesting that the inclusion of the vaccine and adjuvant ameliorated the toxicity of AmpB to some degree. In addition, the ChimT vaccine alone stimulated in vitro murine macrophages to significantly kill three different internalized species of Leishmania parasites and to produce Th1-type cytokines into the culture supernatants. To conclude, our data suggest that the combination of ChimT/MPLA/AmpB could be considered for further studies as an immunotherapy for L. infantum infection.

Funder

Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Brazil

Publisher

MDPI AG

Subject

General Agricultural and Biological Sciences,General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology

Reference54 articles.

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2. (2023, March 30). World-Health-Organisation. Available online: http://www.who.int/topics/leishmaniasis/en/.

3. Leishmaniases of the New World: Current concepts and implications for future research;Grimaldi;Clin. Microbiol. Rev.,1993

4. Developments in diagnosis and treatment of visceral leishmaniasis during the last decade and future prospects;Ejazi;Expert Rev. Anti-Infect. Ther.,2013

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