Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-28T06:54:52.209Z Has data issue: false hasContentIssue false

Immunochemotherapy for visceral leishmaniasis: combinatorial action of Miltefosine plus LBSapMPL vaccine improves adaptative Th1 immune response with control of splenic parasitism in experimental hamster model

Published online by Cambridge University Press:  02 November 2021

Lívia Mendes Carvalho
Affiliation:
Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas/NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil
Miriã Rodrigues Gusmão
Affiliation:
Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas/NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil
Ana Flávia Pereira Costa
Affiliation:
Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas/NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil
Rory Cristiane Fortes de Brito
Affiliation:
Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas/NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil
Rodrigo Dian de Oliveira Aguiar-Soares
Affiliation:
Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas/NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil
Jamille Mirelle de Oliveira Cardoso
Affiliation:
Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas/NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil
Alexandre Barbosa Reis
Affiliation:
Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas/NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais, Salvador, Bahia, Brazil
Cláudia Martins Carneiro
Affiliation:
Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas/NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil
Bruno Mendes Roatt*
Affiliation:
Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas/NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais, Salvador, Bahia, Brazil Departamento de Ciências Biológicas, Instituto de Ciências Exatas e Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
*
Author for correspondence: Bruno Mendes Roatt, E-mail: [email protected]

Abstract

The control of human visceral leishmaniasis (VL) is hard since there are no vaccines available as well as the treatment is hampered by toxicity and resistant parasites. Furthermore, as human, and canine VL causes immunosuppression, the combination of drugs with immunostimulatory agents is interesting to upregulate the immunity, reducing side-effects, improving treatment approaches against disease. Herein, we assessed the immunochemotherapy using miltefosine along with a vaccine formulated by Leishmania braziliensis antigens + saponin + monophosphoryl lipid-A (LBSapMPL) in L. infantum-infected hamsters. Two months after infection, the animals received treatments, and after 15 days they were evaluated for the treatment effect. The potential anti-Leishmania effect of miltefosine + LBSapMPL-vaccine was revealed by a specific immune response activation reflecting in control of spleen parasitism using half the miltefosine treatment time. The treated animals also showed an increase of total and T-CD4 splenocytes producing IFN-γ and TNF-α and a decrease of interleukin-10 and anti-Leishmania circulating IgG. In addition, it was demonstrated that the control of spleen parasitism is related to the generation of a protective Th1 immune response. Hence, due to the combinatorial action of miltefosine with LBSapMPL-vaccine in immunostimulating and controlling parasitism, this immunochemotherapy protocol can be an important alternative option against canine and human VL.

Type
Research Article
Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Aruleba, RT, Carter, KC, Brombacher, F and Hurdayal, R (2020) Can we harness immune responses to improve drug treatment in leishmaniasis? Microorganisms 8, 10691086. doi: 10.3390/microorganisms8071069CrossRefGoogle ScholarPubMed
Borja-Cabrera, GP, Santos, FN, Santos, FB, Trivellato, FA, Kawasaki, JK, Costa, AC, Castro, T, Nogueira, FS, Moreira, MA, Luvizotto, MC, Palatnik, M and Palatnik-de-Sousa, CB (2010) Immunotherapy with the saponin enriched-Leishmune vaccine versus immunochemotherapy in dogs with natural canine visceral leishmaniasis. Vaccine 28, 597603.CrossRefGoogle ScholarPubMed
Carnielli, JBT, Monti-Rocha, R, Costa, DL, Molina Sesana, A, Pansini, LNN, Segatto, M, Mottram, JC, Costa, CHN, Carvalho, SFG and Dietze, R (2019) Natural resistance of Leishmania infantum to miltefosine contributes to the low efficacy in the treatment of visceral leishmaniasis in Brazil. American Journal of Tropical Medicine and Hygiene 101, 789794.CrossRefGoogle Scholar
Carvalho, LM, De Brito, RCF, Gusmao, MR, de Oliveira Aguiar-Soares, RD, Reis, AB and Roatt, BM (2021) Establishment of monoclonal antibodies to evaluate the cellular immunity in a hamster model of L infantum infection. Parasite Immunology 43, e12823. doi: 10.1111/pim.12823CrossRefGoogle Scholar
Croft, SL, Neal, RA, Pendergast, W and Chan, JH (1987) The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani. Biochemical Pharmacology 36, 26332636.CrossRefGoogle ScholarPubMed
da Silva, JC, Nunes, JB, Gontijo, VS, Malaquias, LCC, de Freitas, RP, Alves, RB, Colombo, FA, Laurenti, MD and Marques, MJ (2020) Leishmanicidal activity in vivo of a Miltefosine derivative in Mesocricetus auratus. Acta Tropica 209, 105539.CrossRefGoogle ScholarPubMed
Dayakar, A, Chandrasekaran, S, Kuchipudi, SV and Kalangi, SK (2019) Cytokines: key determinants of resistance or disease progression in visceral leishmaniasis: opportunities for novel diagnostics and immunotherapy. Frontiers in Immunology 10, 670.CrossRefGoogle ScholarPubMed
de Carvalho, CA, Ferrao, TF, Cavalcante, FS, de Freitas, FRN, Meireles, LR and de Andrade Junior, HF (2020) Early high avidity specific IgG production in experimental hamster visceral leishmaniasis. Parasitology Research 119, 38813885.CrossRefGoogle ScholarPubMed
Eberhardt, E, Mondelaers, A, Hendrickx, S, Van den Kerkhof, M, Maes, L and Caljon, G (2016) Molecular detection of infection homogeneity and impact of miltefosine treatment in a Syrian golden hamster model of Leishmania donovani and L. infantum visceral leishmaniasis. Parasitology Research 115, 40614070.CrossRefGoogle Scholar
Freitas-Junior, LH, Chatelain, E, Kim, HA and Siqueira-Neto, JL (2012) Visceral leishmaniasis treatment: what do we have, what do we need and how to deliver it? International Journal for Parasitology. Drugs and Drug Resistance 2, 1119.CrossRefGoogle Scholar
Garcon, N and Di Pasquale, A (2017) From discovery to licensure, the adjuvant system story. Human Vaccines & Immunotherapeutics 13, 1933.CrossRefGoogle ScholarPubMed
Garcon, N and Van Mechelen, M (2011) Recent clinical experience with vaccines using MPL- and QS-21-containing adjuvant systems. Expert Review of Vaccines 10, 471486.CrossRefGoogle ScholarPubMed
Giunchetti, RC, Silveira, P, Resende, LA, Leite, JC, Melo-Junior, OAO, Rodrigues-Alves, ML, Costa, LM, Lair, DF, Chaves, VR, Soares, IDS, de Mendonca, LZ, Lanna, MF, Ribeiro, HS, Maia-Goncalves, AA, Santos, TAP, Roatt, BM, Aguiar-Soares, RDO, Vitoriano-Souza, J, das Dores Moreira, N, Mathias, FAS, Cardoso, JMO, Coura-Vital, W, Galdino, AS, Viana, KF, Martins-Filho, OA, Silveira-Lemos, DD, Dutra, WO and Reis, AB (2019) Canine visceral leishmaniasis biomarkers and their employment in vaccines. Veterinary Parasitology 271, 8797.CrossRefGoogle ScholarPubMed
Gupta, R, Kushawaha, PK, Samant, M, Jaiswal, AK, Baharia, RK and Dube, A (2012) Treatment of Leishmania donovani-infected hamsters with miltefosine: analysis of cytokine mRNA expression by real-time PCR, lymphoproliferation, nitrite production and antibody responses. Journal of Antimicrobial Chemotherapy 67, 440443.CrossRefGoogle ScholarPubMed
Hart, PH, Whitty, GA, Piccoli, DS and Hamilton, JA (1989) Control by IFN-gamma and PGE2 of TNF alpha and IL-1 production by human monocytes. Immunology 66, 376383.Google ScholarPubMed
Joshi, J, Malla, N and Kaur, S (2014) A comparative evaluation of efficacy of chemotherapy, immunotherapy and immunochemotherapy in visceral leishmaniasis-an experimental study. Parasitology International 63, 612620.CrossRefGoogle ScholarPubMed
Lowry, OH, Rosebrough, NJ, Farr, AL and Randall, RJ (1951) Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry 193, 265275.CrossRefGoogle ScholarPubMed
Lukes, J, Mauricio, IL, Schonian, G, Dujardin, JC, Soteriadou, K, Dedet, JP, Kuhls, K, Tintaya, KW, Jirku, M, Chocholova, E, Haralambous, C, Pratlong, F, Obornik, M, Horak, A, Ayala, FJ and Miles, MA (2007) Evolutionary and geographical history of the Leishmania donovani complex with a revision of current taxonomy. Proceedings of the National Academy of Sciences of the USA 104, 93759380.CrossRefGoogle ScholarPubMed
Mayrink, W, Botelho, AC, Magalhaes, PA, Batista, SM, Lima Ade, O, Genaro, O, Costa, CA, Melo, MN, Michalick, MS, Williams, P, Dias, M, Caiaffa, WT, Nascimento, E and Machado-Coelho, GL (2006) Immunotherapy, immunochemotherapy and chemotherapy for American cutaneous leishmaniasis treatment. Revista da Sociedade Brasileira de Medicina Tropical 39, 1421.CrossRefGoogle ScholarPubMed
Medina-Colorado, AA, Osorio, EY, Saldarriaga, OA, Travi, BL, Kong, F, Spratt, H, Soong, L and Melby, PC (2017) Splenic CD4+ T cells in progressive visceral leishmaniasis show a mixed effector-regulatory phenotype and impair macrophage effector function through inhibitory receptor expression. PLoS ONE 12, e0169496.CrossRefGoogle ScholarPubMed
Moreira, N, Vitoriano-Souza, J, Roatt, BM, Vieira, PM, Ker, HG, de Oliveira Cardoso, JM, Giunchetti, RC, Carneiro, CM, de Lana, M and Reis, AB (2012) Parasite burden in hamsters infected with two different strains of leishmania (Leishmania) infantum: ‘Leishman Donovan units’ versus real-time PCR. PLoS ONE 7, e47907.CrossRefGoogle Scholar
Mosmann, TR (1991) Cytokine secretion patterns and cross-regulation of T cell subsets. Immunologic Research 10, 183188.CrossRefGoogle ScholarPubMed
Moulik, S, Karmakar, J, Joshi, S, Dube, A, Mandal, C and Chatterjee, M (2021) Status of IL-4 and IL-10 driven markers in experimental models of visceral leishmaniasis. Parasite Immunology 43, e12783.CrossRefGoogle ScholarPubMed
Musa, AM, Noazin, S, Khalil, EA and Modabber, F (2010) Immunological stimulation for the treatment of leishmaniasis: a modality worthy of serious consideration. Transactions of the Royal Society of Tropical Medicine and Hygiene 104, 12.CrossRefGoogle ScholarPubMed
Nathan, CF and Hibbs, JB Jr. (1991). Role of nitric oxide synthesis in macrophage antimicrobial activity. Current Opinion in Immunology 3, 6570.CrossRefGoogle ScholarPubMed
Neogy, AB, Nandy, A, Ghosh Dastidar, B and Chowdhury, AB (1987) Antibody kinetics in kala-azar in response to treatment. Annals of Tropical Medicine & Parasitology 81, 727729.CrossRefGoogle ScholarPubMed
PAHO (2017) Epidemiological Report of the Americas. Leishmaniases, April 2017. pp. 8.Google Scholar
Palic, S, Bhairosing, P, Beijnen, JH and Dorlo, TPC (2019) Systematic review of host-mediated activity of miltefosine in leishmaniasis through immunomodulation. Antimicrobial Agents and Chemotherapy 63, e02507–18. doi: 10.1128/AAC.02507-18.CrossRefGoogle ScholarPubMed
Rawat, K, Yadav, NK, Joshi, S, Ratnapriya, S, Sahasrabuddhe, AA and Dube, A (2018) Immunotherapeutic potential of Leishmania (Leishmania) donovani Th1 stimulatory proteins against experimental visceral leishmaniasis. Vaccine 36, 22932299. doi: 10.1016/j.vaccine.2018.03.027Google Scholar
Reis, AB, Teixeira-Carvalho, A, Vale, AM, Marques, MJ, Giunchetti, RC, Mayrink, W, Guerra, LL, Andrade, RA, Correa-Oliveira, R and Martins-Filho, OA (2006) Isotype patterns of immunoglobulins: hallmarks for clinical status and tissue parasite density in Brazilian dogs naturally infected by Leishmania (Leishmania) chagasi. Veterinary Immunology and Immunopathology 112, 102116.CrossRefGoogle ScholarPubMed
Reis, AB, Martins-Filho, OA, Teixeira-Carvalho, A, Giunchetti, RC, Carneiro, CM, Mayrink, W, Tafuri, WL and Correa-Oliveira, R (2009) Systemic and compartmentalized immune response in canine visceral leishmaniasis. Veterinary Immunology and Immunopathology 128, 8795.CrossRefGoogle ScholarPubMed
Reis, AB, Giunchetti, RC, Carrillo, E, Martins-Filho, OA and Moreno, J (2010) Immunity to Leishmania and the rational search for vaccines against canine leishmaniasis. Trends in Parasitology 26, 341349.CrossRefGoogle ScholarPubMed
Roatt, BM, Aguiar-Soares, RD, Reis, LE, Cardoso, JM, Mathias, FA, de Brito, RC, da Silva, SM, Gontijo, NF, Ferreira, SA, Valenzuela, JG, Correa-Oliveira, R, Giunchetti, RC and Reis, AB (2017) A vaccine therapy for canine visceral leishmaniasis promoted significant improvement of clinical and immune status with reduction in parasite burden. Frontiers in Immunology 8, 217.CrossRefGoogle ScholarPubMed
Roatt, BM, de Oliveira Cardoso, JM, De Brito, RCF, Coura-Vital, W, de Oliveira Aguiar-Soares, RD and Reis, AB (2020) Recent advances and new strategies on leishmaniasis treatment. Applied Microbiology and Biotechnology 104, 89658977.CrossRefGoogle ScholarPubMed
Shivahare, R, Vishwakarma, P, Parmar, N, Yadav, PK, Haq, W, Srivastava, M, Gupta, S and Kar, S (2014) Combination of liposomal CpG oligodeoxynucleotide 2006 and miltefosine induces strong cell-mediated immunity during experimental visceral leishmaniasis. PLoS ONE 9, e94596.CrossRefGoogle ScholarPubMed
Srivastava, S, Mishra, J, Gupta, AK, Singh, A, Shankar, P and Singh, S (2017) Laboratory confirmed miltefosine resistant cases of visceral leishmaniasis from India. Parasites & Vectors 10, 49.CrossRefGoogle ScholarPubMed
Sundar, S and Singh, A (2018) Chemotherapeutics of visceral leishmaniasis: present and future developments. Parasitology 145, 481489.CrossRefGoogle ScholarPubMed
Sundar, S, Jha, TK, Thakur, CP, Engel, J, Sindermann, H, Fischer, C, Junge, K, Bryceson, A and Berman, J (2002) Oral miltefosine for Indian visceral leishmaniasis. New England Journal of Medicine 347, 17391746.CrossRefGoogle ScholarPubMed
Unger, C, Damenz, W, Fleer, EA, Kim, DJ, Breiser, A, Hilgard, P, Engel, J, Nagel, G and Eibl, H (1989) Hexadecylphosphocholine, a new ether lipid analogue. Studies on the antineoplastic activity in vitro and in vivo. Acta Oncologica (Stockholm, Sweden) 28, 213217.CrossRefGoogle ScholarPubMed
WHO (2017) Integrating Neglected Tropical Diseases into Global Health and Development: Fourth WHO Report on Neglected Tropical Diseases: Executive Summary. World Health Organization. https://apps.who.int/iris/handle/10665/255013Google Scholar
Zulfiqar, B, Shelper, TB and Avery, VM (2017) Leishmaniasis drug discovery: recent progress and challenges in assay development. Drug Discovery Today 22, 15161531.CrossRefGoogle ScholarPubMed
Supplementary material: Image

Carvalho et al. supplementary material

Carvalho et al. supplementary material 1

Download Carvalho et al. supplementary material(Image)
Image 242.1 KB
Supplementary material: Image

Carvalho et al. supplementary material

Carvalho et al. supplementary material 2

Download Carvalho et al. supplementary material(Image)
Image 96 KB
Supplementary material: File

Carvalho et al. supplementary material

Carvalho et al. supplementary material 3

Download Carvalho et al. supplementary material(File)
File 13.9 KB