Abstract
Background
Chagas disease or American trypanosomiasis is caused by the protozoan Trypanosoma cruzi and is endemic of the Americas. The control of the disease is restricted to toxic and potentially teratogenic drugs, which limit the use during pregnancy. The use of food supplementation offers a safe and low-cost form to alleviate Chagas disease symptoms, mostly in areas with alimentary risk. For example, zinc demonstrates positive effects in immune response, including in Chagas disease during pregnancy.
Purpose
This study describes the innate response in pregnant rats chronically infected with T. cruzi and supplemented with zinc.
Methods
Pregnant female Wistar rats, infected with T. cruzi, were treated with 20 mg/kg/day zinc sulfate and euthanized on the 18th day. Samples (plasma, splenocytes, and peritoneal exudate) were collected and several immune parameters (nitric oxide, RT1B, CD80/CD86, MCP-1, CD11b/c, NK/NKT, IL-2, IL-10, INF-cc, and apoptosis) evaluated.
Results
Under Zinc supplementation and/or T. cruzi infection, the gestation developed normally. Several innate immune parameters such as RT1B, CD80/CD86, MCP-1 expressing lymphocytes, IL-2, and IL-17 were positively altered, whereas nitric oxide, CD11b/c, NK/NKT, apoptosis, INF-γ, and corticosterone demonstrated a pro-pregnancy pattern.
Conclusion
Our results indicated that zinc has diverse effects on immune response during pregnancy. An anti-T. cruzi immunity, as well as a pro-gestation response, were observed after zinc supplementation. The complete comprehension of zinc supplementation in pregnancy will base an adequate strategy to alleviate Chagas disease symptoms and propagation, especially for populations from endemic areas.
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8. References
Abrahams VM, Straszewski-Chavez SL, Guller S, Mor G (2004) First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis. Mol Hum Reprod 10:55–63. https://doi.org/10.1093/molehr/gah006
Bartmann C, Segerer SE, Rieger L, Kapp M, Sutterlin M, Kammerer U (2014) Quantification of the predominant immune cell populations in decidua throughout human pregnancy. Am J Reprod Immunol 71:109–119. https://doi.org/10.1111/aji.12185
Batista BL, Rodrigues JL, Nunes JA, Souza VC, Barbosa F Jr (2009) Exploiting dynamic reaction cell inductively coupled plasma mass spectrometry (DRC-ICP-MS) for sequential determination of trace elements in blood using a dilute-and-shoot procedure. Anal Chim Acta 639:13–18. https://doi.org/10.1016/j.aca.2009.03.016
Benevides L, Milanezi CM, Yamauchi LM, Benjamim CF, Silva JS, Silva NM (2008) CCR2 receptor is essential to activate microbicidal mechanisms to control Toxoplasma gondii infection in the central nervous system. Am J Pathol 173:741–751. https://doi.org/10.2353/ajpath.2008.080129
Bryan NS, Grisham MB (2007) Methods to detect nitric oxide and its metabolites in biological samples. Free Radic Biol Med 43:645–657. https://doi.org/10.1016/j.freeradbiomed.2007.04.026
Cardillo F, Voltarelli JC, Reed SG, Silva JS (1996) Regulation of Trypanosoma cruzi infection in mice by gamma interferon and interleukin 10: role of NK cells. Infect Immun 64:128–134
Carvalho CM, Silverio JC, da Silva AA, Pereira IR, Coelho JM, Britto CC, Moreira OC, Marchevsky RS, Xavier SS, Gazzinelli RT, da Gloria B-A, Lannes-Vieira J (2012) Inducible nitric oxide synthase in heart tissue and nitric oxide in serum of Trypanosoma cruzi-infected rhesus monkeys: association with heart injury. PLoS Negl Trop Dis 6:e1644. https://doi.org/10.1371/journal.pntd.0001644
Chakraborty D, Rumi MA, Konno T, Soares MJ (2011) Natural killer cells direct hemochorial placentation by regulating hypoxia-inducible factor dependent trophoblast lineage decisions. Proc Natl Acad Sci USA 108:16295–16300. https://doi.org/10.1073/pnas.1109478108
Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME (2012) Zinc and human health: an update. Arch Toxicol 86:521–534. https://doi.org/10.1007/s00204-011-0775-1
Chen L, Flies DB (2013) Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 13:227–242. https://doi.org/10.1038/nri3405
Correa VR, Barbosa FG, Melo Junior CA, D'Albuquerque e Castro LF, Andrade Junior HF, Nascimento N (2014) Uneventful benznidazole treatment of acute Chagas disease during pregnancy: a case report. Rev Soc Bras Med Trop 47:397–400
da Costa CM, Brazao V, Collins Kuehn C, Rodrigues Oliveira LG, do Prado Junior JC, Sala MA, Abrahao AAC (2013) Zinc and pregnancy: Marked changes on the immune response following zinc therapy for pregnant females challenged with Trypanosoma cruzi. Clin Nutr 32:592–598. https://doi.org/10.1016/j.clnu.2012.10.012
da Costa CMB, Pereira LM, Barbosa Jr F, do Prado JC, Abrahão AAC (2017) Chagas disease control and role of zinc supplementation in pregnancy. Matters. https://doi.org/10.19185/matters.201612000008
da Costa CMB, Del Vecchio FM, Santello FH, Pereira LM, Toldo MPA, do Prado Junior JC, Abrahao AAC (2018) Is the adaptive immune response in murine Trypanosoma cruzi infection influenced by zinc supplementation? Eur J Pharm Sci 111:330–336. https://doi.org/10.1016/j.ejps.2017.10.014
Darmochwal-Kolarz D, Michalak M, Kolarz B, Przegalinska-Kalamucka M, Bojarska-Junak A, Sliwa D, Oleszczuk J (2017) The role of interleukin-17, interleukin-23, and transforming growth factor-beta in pregnancy complicated by placental insufficiency. Biomed Res Int 2017:6904325. https://doi.org/10.1155/2017/6904325
Decote-Ricardo D, Nunes MP, Morrot A, Freire-de-Lima CG (2017) Implication of apoptosis for the pathogenesis of Trypanosoma cruzi infection. Front Immunol 8:518. https://doi.org/10.3389/fimmu.2017.00518
Duthie MS, Kahn SJ (2005) NK cell activation and protection occur independently of natural killer T cells during Trypanosoma cruzi infection. Int Immunol 17:607–613. https://doi.org/10.1093/intimm/dxh239
Erdmann H, Rossnagel C, Bohme J, Iwakura Y, Jacobs T, Schaible UE, Holscher C (2013) IL-17A promotes macrophage effector mechanisms against Trypanosoma cruzi by trapping parasites in the endolysosomal compartment. Immunobiology 218:910–923. https://doi.org/10.1016/j.imbio.2012.10.005
Erdmann H, Behrends J, Holscher C (2016) During acute experimental infection with the reticulotropic Trypanosoma cruzi strain Tulahuen IL-22 is induced IL-23-dependently but is dispensable for protection. Sci Rep 6:32927. https://doi.org/10.1038/srep32927
Fraccaroli L, Alfieri J, Larocca L, Calafat M, Mor G, Leirós CP, Ramhorst R (2009) A potential tolerogenic immune mechanism in a trophoblast cell line through the activation of chemokine-induced T cell death and regulatory T cell modulation. Hum Reprod 24:166–175. https://doi.org/10.1093/humrep/den344
Gil-Jaramillo N, Motta FN, Favali CB, Bastos IM, Santana JM (2016) Dendritic cells: a double-edged sword in immune responses during Chagas disease. Front Microbiol 7:1076. https://doi.org/10.3389/fmicb.2016.01076
Haase H, Rink L (2014) Multiple impacts of zinc on immune function. Metallomics 6:1175–1180. https://doi.org/10.1039/c3mt00353a
Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, Mineau F, Pelletier JP (1998) IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol 160:3513–3521
Kaminski VL, Ellwanger JH, Chies JAB (2019) Extracellular vesicles in host-pathogen interactions and immune regulation—exosomes as emerging actors in the immunological theater of pregnancy. Heliyon 5:e02355. https://doi.org/10.1016/j.heliyon.2019.e02355
Keen CL, Clegg MS, Hanna LA, Lanoue L, Rogers JM, Daston GP, Oteiza P, Uriu-Adams JY (1605s) The plausibility of micronutrient deficiencies being a significant contributing factor to the occurrence of pregnancy complications. J Nutr 133:1597s–1605s. https://doi.org/10.1093/jn/133.5.1597S
Kuziel WA, Morgan SJ, Dawson TC, Griffin S, Smithies O, Ley K, Maeda N (1997) Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc Natl Acad Sci USA 94:12053–12058
Liu W, Yuen EY, Yan Z (2010) The stress hormone corticosterone increases synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors via serum- and glucocorticoid-inducible kinase (SGK) regulation of the GDI-Rab4 complex. J Biol Chem 285:6101–6108. https://doi.org/10.1074/jbc.M109.050229
Marcipar IS, Risso MG, Silber AM, Revelli S, Marcipar AJ (2001) Antibody maturation in Trypanosoma cruzi-infected rats. Clin Diagn Lab Immunol 8(4):802–805. https://doi.org/10.1128/CDLI.8.4.802-805.2001
Miyahira Y, Katae M, Kobayashi S, Takeuchi T, Fukuchi Y, Abe R, Okumura K, Yagita H, Aoki T (2003) Critical contribution of CD28-CD80/CD86 costimulatory pathway to protection from Trypanosoma cruzi infection. Infect Immun 71:3131–3137
Miyazaki Y, Hamano S, Wang S, Shimanoe Y, Iwakura Y, Yoshida H (2010) IL-17 is necessary for host protection against acute-phase Trypanosoma cruzi infection. J Immunol 185:1150–1157. https://doi.org/10.4049/jimmunol.0900047
Mor G, Cardenas I (2010) The immune system in pregnancy: a unique complexity. Am J Reprod Immunol 63:425–433. https://doi.org/10.1111/j.1600-0897.2010.00836.x
Oliveira LRC, Picka MCM, Nicolete VC, Calvi SA, Marcondes-Machado J (2012) Organ tropism during the acute and chronic phases of Trypanosoma cruzi infection in BALB/c mice. J Venom Anim Toxins incl Trop Dis 18:34–43. https://doi.org/10.1590/S1678-91992012000100005
Van Overtvelt L, Andrieu M, Verhasselt V, Connan F, Choppin J, Vercruysse V, Goldman M, Hosmalin A, Vray B (2002) Trypanosoma cruzi down-regulates lipopolysaccharide-induced MHC class I on human dendritic cells and impairs antigen presentation to specific CD8(+) T lymphocytes. Int Immunol 14:1135–1144
Paiva CN, Figueiredo RT, Kroll-Palhares K, Silva AA, Silverio JC, Gibaldi D, Pyrrho Ados S, Benjamim CF, Lannes-Vieira J, Bozza MT (2009) CCL2/MCP-1 controls parasite burden, cell infiltration, and mononuclear activation during acute Trypanosoma cruzi infection. J Leukoc Biol 86:1239–1246. https://doi.org/10.1189/jlb.0309187
Pereira M, Soares C, Canuto GA, Tavares MF, Colli W, Alves MJ (2015) Down regulation of NO signaling in Trypanosoma cruzi upon parasite-extracellular matrix interaction: changes in protein modification by nitrosylation and nitration. PLoS Negl Trop Dis 9:e0003683. https://doi.org/10.1371/journal.pntd.0003683
Perez AR, Bertoya AA, Revelli S, Garcia F (2011) A high corticosterone/DHEA-s ratio in young rats infected with Trypanosoma cruzi is associated with increased susceptibility. Mem Inst Oswaldo Cruz 106:416–423
Prasad AS (1995) Zinc: an overview. Nutrition 11:93–99
Robben PM, LaRegina M, Kuziel WA, Sibley LD (2005) Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis. J Exp Med 201:1761–1769. https://doi.org/10.1084/jem.20050054
Rottenberg M, Cardoni RL, Andersson R, Segura EL, Orn A (1988) Role of T helper/inducer cells as well as natural killer cells in resistance to Trypanosoma cruzi infection. Scand J Immunol 28:573–582
Sales Junior PA, Molina I, Fonseca Murta SM, Sanchez-Montalva A, Salvador F, Correa-Oliveira R, Carneiro CM (2017) Experimental and clinical treatment of chagas disease: a review. Am J Trop Med Hyg 97:1289–1303. https://doi.org/10.4269/ajtmh.16-0761
Schroder K, Hertzog PJ, Ravasi T, Hume DA (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75:163–189. https://doi.org/10.1189/jlb.0603252
Serbina NV, Jia T, Hohl TM, Pamer EG (2008) Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol 26:421–452. https://doi.org/10.1146/annurev.immunol.26.021607.090326
Silva LHP, Nussenzweig V (1953) Sobre uma cepa de Trypanosoma cruzi altamente virulenta para o camundongo branco. Folia clinica et biologica 20:191–207
Sisti G, Kanninen TT, Witkin SS (2016) Maternal immunity and pregnancy outcome: focus on preconception and autophagy. Genes Immun 17:1–7. https://doi.org/10.1038/gene.2015.57
Sundareswaran L, Srinivasan S, Wankhar W, Sheeladevi R (2017) Effect of Scoparia dulcis on noise stress induced adaptive immunity and cytokine response in immunized Wistar rats. J Ayurv Integr Med 8:13–19. https://doi.org/10.1016/j.jaim.2016.10.004
Sykes L, MacIntyre DA, Yap XJ, Ponnampalam S, Teoh TG, Bennett PR (2012) Changes in the Th1:Th2 cytokine bias in pregnancy and the effects of the anti-inflammatory cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J2. Mediat Inflamm 2012:416739. https://doi.org/10.1155/2012/416739
Teixeira MM, Gazzinelli RT, Silva JS (2002) Chemokines, inflammation and Trypanosoma cruzi infection. Trends Parasitol 18:262–265
Tezabwala BU, Johnson PM, Rees RC (1989) Inhibition of pregnancy viability in mice following IL-2 administration. Immunology 67:115–119
Totemeyer S, Sheppard M, Lloyd A, Roper D, Dowson C, Underhill D, Murray P, Maskell D, Bryant C (2006) IFN-gamma enhances production of nitric oxide from macrophages via a mechanism that depends on nucleotide oligomerization domain-2. J Immunol 176:4804–4810
Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Physiol Rev 73:79–118. https://doi.org/10.1152/physrev.1993.73.1.79
Vaughan OR, Sferruzzi-Perri AN, Fowden AL (2012) Maternal corticosterone regulates nutrient allocation to fetal growth in mice. J Physiol 590:5529–5540. https://doi.org/10.1113/jphysiol.2012.239426
Vespa GN, Cunha FQ, Silva JS (1994) Nitric oxide is involved in control of Trypanosoma cruzi-induced parasitemia and directly kills the parasite in vitro. Infect Immun 62:5177–5182
World Health Organization (2018) Chagas disease (American trypanosomiasis). Retrieved from World Health Organization website. https://www.who.int/mediacentre/factsheets/fs340/en/. Accessed 14 May 2018
Xu YY, Wang SC, Li DJ, Du MR (2017) Co-signaling molecules in maternal-fetal immunity. Trends Mol Med 23:46–58. https://doi.org/10.1016/j.molmed.2016.11.001
Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Spriggs MK, Armitage RJ (1995) Human IL-17: a novel cytokine derived from T cells. J Immunol 155:5483–5486
Acknowledgements
We would like to thank FAPESP for the fellowship to C.M.B. da Costa (Grant number: 2013/04205-6). We also thank Fabiana Rosetto Morais and Vanessa Cristina de Oliveira Souza for the flow cytometry and HPLC assistance, respectively.
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CMBDC, JCDPJ, and AACA designed the experiments, wrote, and revised the manuscript. CMBDC, MVF, FS, and IFLG carried out the experimental work. LMP and FBJ analyzed the data, wrote, and revised the manuscript. All authors read and approved the final manuscript.
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Bronzon da Costa, C.M., del Vecchio Filipin, M., Santello, F.H. et al. Zinc Supplementation: Immune Balance of Pregnancy During the Chronic Phase of the Chagas Disease. Acta Parasit. 65, 599–609 (2020). https://doi.org/10.2478/s11686-020-00188-0
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DOI: https://doi.org/10.2478/s11686-020-00188-0