Hostname: page-component-586b7cd67f-l7hp2 Total loading time: 0 Render date: 2024-11-22T16:10:28.298Z Has data issue: false hasContentIssue false

Prospection of immunological biomarkers for characterization and monitoring of asymptomatic Leishmania (Leishmania) infantum infection

Published online by Cambridge University Press:  28 May 2020

Gisele Macêdo Rodrigues da Cunha
Affiliation:
Laboratório de Epidemiologia de Doenças Infecciosas e Parasitárias, Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil
Mariângela Carneiro*
Affiliation:
Laboratório de Epidemiologia de Doenças Infecciosas e Parasitárias, Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil Pós-graduação em Ciências da Saúde, Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil
Marcelo Antônio Pascoal-Xavier
Affiliation:
Grupo Imunologia de Doenças Virais, Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), 30190-002, Belo Horizonte, MG, Brazil Laboratório de Patologia Molecular, Departamento de Anatomia Patológica, Faculdade de Medicina, Universidade Federal de Minas Gerais, 30130-100, Belo Horizonte, MG, Brazil
Iara Caixeta Marques da Rocha
Affiliation:
Laboratório de Epidemiologia de Doenças Infecciosas e Parasitárias, Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil
Fernanda do Carmo Magalhães
Affiliation:
Laboratório de Epidemiologia de Doenças Infecciosas e Parasitárias, Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil
Olindo Assis Martins-Filho
Affiliation:
Grupo Integrado de Pesquisas em Biomarcadores, Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), 30190-002, Belo Horizonte, MG, Brazil
Edward Oliveira
Affiliation:
Pesquisa Clínica e Políticas Públicas em Doenças Infecciosas e Parasitárias, Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), 30190-002, Belo Horizonte, MG, Brazil
Vanessa Peruhype-Magalhães
Affiliation:
Grupo Integrado de Pesquisas em Biomarcadores, Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), 30190-002, Belo Horizonte, MG, Brazil
*
Author for correspondence: Mariângela Carneiro, E-mail: [email protected]

Abstract

In areas endemic for Leishmania infantum, an asymptomatic infection may be an indicator of the extent of transmission. The main goal of this study was to evaluate the applicability of measuring circulating immunological biomarkers as an alternative strategy to characterize and monitor L. infantum asymptomatic infections in combination with serological methods. To this end, 179 children from a region endemic for visceral leishmaniasis (VL), aged 1–10 years old, selected from a cross-sectional study, were identified as asymptomatic (n = 81) or uninfected (n = 98) by qPCR and/or serological tests (ELISA using L. infantum soluble antigen and rK39), and, together with serum samples of children diagnosed with VL (n = 43), were subjected to avidity tests and cytokine levels measurement. Avidity rates (AR) ranging from 41 to 70% were found in 29 children (66%) from the asymptomatic group. On the other hand, high AR (above 70%) were observed in 27 children (64%) from the VL group. Logistic Regression and Classification and Regression Tree (CART) analyses demonstrated that lower AR and IFN-γ production associated with higher IL-17A levels were hallmarks in asymptomatic L. infantum infections. Therefore, this study proposes an association of immunological biomarkers that can be used as a complementary strategy for the characterization and monitoring of asymptomatic VL infections in children living in endemic areas.

Type
Research Article
Copyright
Copyright © The Author(s), 2020. 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

Alvar, J, Vélez, ID, Bern, C, Herrero, M, Desjeux, P, Cano, J, Jannin, J and de Boer, M (2012) Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 7, e35671.CrossRefGoogle ScholarPubMed
Badaro, R, Jones, TC, Carvalho, EM, Sampaio, D, Reed, SG, Barral, A, Teixeira, R and Johnson, WD Jr (1986) New perspectives on a subclinical form of visceral leishmaniasis. Journal of Infectious Diseases 148, 10031011.CrossRefGoogle Scholar
Badaró, R, Benson, D, Eulálio, MC, Freire, M, Cunha, S, Netto, EM, Pedral-Sampaio, D, Madureira, C, Burns, JM, Houghton, RL, David, JR and Reed, SG (1996) Rk39: a cloned antigen of Leishmania chagasi that predicts active visceral leishmaniasis. Journal of Infectious Diseases 173, 758761.CrossRefGoogle ScholarPubMed
Braz, RF, Nascimento, ET, Martins, DR, Wilson, ME, Pearson, RD, Reed, SG and Jerônimo, SM (2002) The sensitivity and specificity of Leishmania chagasi recombinant K39 antigen in the diagnosis of American visceral leishmaniasis and in differentiating active from subclinical infection. American Journal of Tropical Medicine and Hygiene 67, 344348.CrossRefGoogle Scholar
Burns, JM, Shreffler, WG, Benson, DR, Ghalibt, HW, Badaro, R and Reed, S (1993) Molecular characterization of a kinesin-related antigen of Leishmania chagasi that detects specific antibody in African and American visceral leishmaniasis. Proceedings of the National Academy of Sciences of the USA 90, 775779.CrossRefGoogle ScholarPubMed
Caldas, AJM, Silva, DRC, Pereira, CCR, Nunes, PMS, Silva, BP, Silva, AAM, Barral, A and Costa, JML (2001) Infecção por Leishmania (Leishmania) chagasi Em crianças de uma área endêmica de leishmaniose visceral americana na Ilha de São Luís – MA, Brasil. Revista da Sociedade Brasileira de Medicina Tropical 34, 1521.CrossRefGoogle Scholar
Costa, CH, Pereira, HF, Pereira, FC, Tavares, JP, Araújo, MV and Gonçalves, MJ (1999) Is the household dog a risk factor for American visceral leishmaniasis in Brasil? Transactions of the Royal Society of Tropical 93, 464.CrossRefGoogle Scholar
Costa, CH, Stewart, JM, Gomes, RB, Garcez, LM, Ramos, PK, Bozza, M, Satoskar, A, Dissanayake, S, Santos, RS, Silva, MR, Shaw, JJ, David, JR and Maguire, JH (2002) Asymptomatic human carriers of Leishmania chagasi. American Journal of Tropical Medicine and Hygiene 66, 334337.CrossRefGoogle ScholarPubMed
Costa, AS, Costa, GC, Aquino, DM, Mendonça, VR, Barral, A, Barral-Netto, M and Caldas Ade, J (2012) Cytokines and visceral leishmaniasis: a comparison of plasma cytokine profiles between the clinical forms of visceral leishmaniasis. Memórias do Instituto Oswaldo Cruz 107, 735739.CrossRefGoogle ScholarPubMed
Costa, DL, Rocha, RL, Carvalho, RM, Lima-Neto, AS, Harhay, MO, Costa, CH, Barral-Neto, M and Barral, AP (2013) Serum cytokines associated with severity and complications of Kala-azar. Pathogens and Global Health 107, 7887.CrossRefGoogle ScholarPubMed
da Rocha, ICM, Dos Santos, LHM, Coura-Vital, W, da Cunha, GMR, Magalhães, FDC, da Silva, TAM, Morais, MHF, Oliveira, E, Reis, IA and Carneiro, M (2018) Effectiveness of the Brazilian Visceral Leishmaniasis Surveillance and Control Programme in reducing the prevalence and incidence of Leishmania infantum infection. Parasites & Vectors 11, 586.CrossRefGoogle ScholarPubMed
de Gouvêa Viana, L, de Assis, TS, Orsini, M, da Silva, AR, de Souza, GF, Caligiorne, R, da Silva, AC, Peruhype-Magalhães, V, Marciano, AP, Martins-Filho, OA and Rabello, A (2008) Combined diagnostic methods identify a remarkable proportion of asymptomatic Leishmania (Leishmania) chagasi carriers who present modulated cytokine profiles. Transactions of the Royal Society of Tropical Medicine and Hygiene 102, 548555.CrossRefGoogle ScholarPubMed
de Souza, MA, da Sil, AG, Afonso-Cardoso, SR, Favoreto, SJ and Ferreira, MS (2005) Immunoglobulin isotype and IgG subclass profiles in American tegumentary leishmaniasis. Revista da Sociedade Brasileira de Medicina Tropical 38, 137141.CrossRefGoogle ScholarPubMed
Dos Santos, PL, de Oliveira, FA, Santos, ML, Cunha, LC, Lino, MT, de Oliveira, MF, Bomfim, MO, Silva, AM, de Moura, TR, de Jesus, AR, Duthie, MS, Reed, SG and de Almeida, RP (2016) The severity of visceral leishmaniasis correlates with elevated levels of serum IL-6, IL-27 and sCD14. PLoS Neglected Tropical Diseases 10, e0004375.CrossRefGoogle ScholarPubMed
dos Santos Marques, LH, Gomes, LI, da Rocha, IC, da Silva, TA, Oliveira, E, Morais, MH, Rabello, A and Carneiro, M (2012) Low parasite load estimated by qPCR in a cohort of children living in urban area endemic for visceral leishmaniasis in Brazil. PLoS Neglected Tropical Diseases 6, e1955.CrossRefGoogle Scholar
Evans, TG, Teixeira, MJ, McAuliffe, IT, Vasconcelos, IAB, Vasconcelos, AW, Sousa, QA, Lima, JWO and Pearson, RD (1992) Epidemiology of visceral leishmaniasis in Northeast Brazil. Journal of Infectious Diseases 166, 11241132.CrossRefGoogle ScholarPubMed
Filisetti, D and Candolf, E (2004) Immune response to Toxoplasma gondi. Annali dell'Istituto Superiore di Sanità 40, 7180.Google Scholar
Galvão-Castro, B, Sá Ferreira, , Marzochi, KF, Marzoch, MC, Coutinho, SG and Lambert, PH (1984) Polyclonal B cell activation, circulating immune complexes and autoimmunity in human American visceral leishmaniasis. Clinical Experimental Immunology 56, 5866.Google ScholarPubMed
Gontijo da Silva, M, Clare Vinaud, M and de Castro, AM (2015) Prevalence of toxoplasmosis in pregnant women and vertical transmission of Toxoplasma gondii in patients from basic units of health from Gurupi, Tocantins, Brazil, from 2012 to 2014. PLoS ONE 10, e0141700.CrossRefGoogle ScholarPubMed
Ho, M, Leeuwenburg, J, Mbugua, G, Wamachi, A and Voller, A (1983) An enzyme-linked immunosorbent assay (ELISA) for field diagnosis of visceral leishmaniasis. American Journal of Tropical Medicine and Hygiene 32, 943946.CrossRefGoogle ScholarPubMed
Ibarra-Meneses, AV, Sanchez, C, Alvar, J, Moreno, J and Carrillo, E (2017) Monocyte chemotactic protein 1 in plasma from soluble leishmania antigen-stimulated whole blood as a potential biomarker of the cellular immune response to Leishmania infantum. Frontiers in Immunology 29, 1208.CrossRefGoogle Scholar
Jerônimo, SM, Teixeira, MJ, Sousa, AD, Thielking, P, Pearson, RD and Evans, TG (2000) Natural history of Leishmania (Leishmania) chagasi infection in northeastern Brazil: long-term follow-up. Clinical Infectious Diseases 30, 608609.CrossRefGoogle ScholarPubMed
Khoshdel, A, Alborzi, A, Rosouli, M, Taheri, E, Kiany, S and Javadian, MH (2009) Increased levels of IL-10, IL-12, and IFN-gamma in patients with visceral leishmaniasis. Brazilian Journal of Infectious Diseases 13, 4446.CrossRefGoogle Scholar
Moreno, EC, Melo, MN, Lambertucci, JR, Serufo, JC, Andrade, AS, Antunes, CM, Genaro, O and Carneiro, M (2006) Diagnosing human asymptomatic visceral leishmaniasis in an urban area of the State of Minas Gerais, using serological and molecular biology techniques. Revista da Sociedade Brasileira de Medicina Tropical 39, 421427.CrossRefGoogle Scholar
Moreno, EC, Gonçalves, AV, Chaves, AV, Melo, MN, Lambertucci, JR, Andrade, AS, Negrão-Corrêa, D, Figueiredo Antunes, CM and Carneiro, M (2009) Inaccuracy of enzyme-linked immunosorbent assay using soluble and recombinant antigens to detect asymptomatic infection by Leishmania infantum. PLoS Neglected Tropical Diseases 3, 536.CrossRefGoogle ScholarPubMed
Musso, O, Sommer, P, Drouet, E, Cotte, L, Neyra, M, Grimaud, J-A and Chevallier, M (1996) In situ detection of human cytomegalovirus DNA in gastrointestinal biopsies from AIDS patients by means of various PCR-derived methods. Journal of Virological Methods 56(2), 125137. http://dx.doi.org/10.1016/0166-0934(95)01892-1CrossRefGoogle ScholarPubMed
Peruhype-Magalhães, V, Martins-Filho, OA, Prata, A, Silva, L, Rabello, A, Teixeira-Carvalho, A, Figueiredo, RM, Guimarães-Carvalho, SF, Ferrari, TC and Correa-Oliveira, R (2005) Immune response in human visceral leishmaniasis: analysis of the correlation between innate immunity cytokine profile and disease outcome. Scandinavian Journal of Immunology 62, 487495.CrossRefGoogle ScholarPubMed
Peruhype-Magalhães, V, Martins-Filho, OA, Prata, A, Silva, LdA, Rabello, A, Teixeira-Carvalho, A, Figueiredo, RM, Guimarães-Carvalho, SF, Ferrari, TC, Van Weyenbergh, J and Correa-Oliveira, R (2006) Mixed inflammatory∕regulatory cytokine profile marked by simultaneous raise of interferon-gamma and interleukin-10 and low frequency of tumour necrosis factor-alpha(+) monocytes are hallmarks of active human visceral leishmaniasis due to Leishmania chagasi infection. Clinical & Experimental Immunology 146, 124132.CrossRefGoogle ScholarPubMed
Pitta, MG, Romano, A, Cabantous, S, Henri, S, Hammad, A, Kouriba, B, Argiro, L, el Kheir, M, Bucheton, B, Mary, C, El-Safi, SH and Dessein, A (2009) IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani. The Journal of Clinical Investigation 119, 23792387.Google ScholarPubMed
Porcino, GN, Carvalho, KSS, Braz, DC, Costa Silva, V, Costa, CHN and de Miranda Santos, IKF (2019) Evaluation of methods for detection of asymptomatic individuals infected with Leishmania infantum in the state of Piauí, Brazil. PLoS Neglected Tropical Diseases 13, e0007493.CrossRefGoogle ScholarPubMed
Redhu, NS, Dey, A, Balooni, V and Singh, S (2006) Use of immunoglobulin G avidity to determine the course of disease in visceral and post-kala-azar dermal leishmaniasis patients. Clinical and Vaccine Immunology 13, 969971.CrossRefGoogle ScholarPubMed
Rodrigues-Neto, JF, Monteiro, GR, Keesen, TSL, Lacerda, HG, Carvalho, EM and Jeronimo, SMB (2018) CD45RO + T cells and T cell activation in the long-lasting immunity after Leishmania infantum infection. The American Journal of Tropical Medicine and Hygiene 98, 875882.CrossRefGoogle Scholar
Romano, A, Cabantous, S, Henri, S, Hammad, A, Kouriba, B, Argiro, L, el Kheir, M, Bucheton, B, Mary, C, El-Safi, SH and Dessein, A (2009) IL-17 and IL-22 are associated with protection against human kala-azar caused by Leishmania donovani. Journal of Clinical Investigation 119, 23792387.Google Scholar
Romero, GA and Boelaert, M (2010) Control of visceral leishmaniasis in Latin America a systematic review. PLoS Neglected Tropical Diseases 4, e584.CrossRefGoogle ScholarPubMed
Singh, S, Kumari, V and Sing, N (2002) Predicting kala-azar disease manifestations in asymptomatic patients with latent Leishmania donovani infection by detection of antibody against recombinant K39 antigen. Clinical and Diagnostic Laboratory Immunology 9, 568572.Google ScholarPubMed
Tiburcio, MG, Anversa, L, Kanunfre, KA, Ferreira, AW, Rodrigues Júnior, V and Silva, LdA (2013) Anti-Leishmania infantum IgG antibody avidity in visceral leishmaniasis. Clinical and Vaccine Immunology 20, 16971702.CrossRefGoogle ScholarPubMed
Van Eys, GJJM, Schoone, GJ, Kroon, CM and Ebeling, SB (1992) Sequence analysis of small subunit RNA genes and its use for detection and identification of Leishmania parasites. Molecular and Biochemical Parasitology 51, 133142.Google ScholarPubMed
WHO (2019) Leishmaniasis Geneva: World Health Organization. WHO. https://www.who.int/leishmaniasis/burden/en/. Last access September 10 2019.Google Scholar
Wortmann, G, Sweeney, C, Houng, HS, Aronson, N, Stiteler, J, Jackson, J and Ockenhouse, C (2001) Rapid diagnosis of leishmaniasis by fluorogenic polymerase chain reaction. American Journal of Tropical Medicine and Hygiene 65, 583587.CrossRefGoogle ScholarPubMed