- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- Effects of AMD and ICZ on infection of Vero cells with T. cruzi strain TcII.
- Effects of AMD and ICZ on infection of hiPSC-CMs with TcII.
- Effects of AMD and ICZ on infection of hiPSC-CMs with TcI.
- Effects of ICZ, AMD, or their combinations on hiPSC-CM metabolism.
- Effects of ICZ, AMD, or their combinations on T. cruzi–infected hiPSC-CM cellular and amastigote structure.
- DISCUSSION
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
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1.
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2.
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A Combination of Itraconazole and Amiodarone Is Highly Effective against Trypanosoma cruzi Infection of Human Stem Cell–Derived Cardiomyocytes
Gabriele Sass
Gabriele Sass
California Institute for Medical Research, San Jose, California;
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Roy T. Madigan
Roy T. Madigan
Animal Hospital of Smithson Valley, Spring Branch, Texas;
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Lydia-Marie Joubert
Lydia-Marie Joubert
Department of Microbiology, Stellenbosch University, Stellenbosch, South Africa;
EM Unit, Central Analytical Facilities, Stellenbosch University, Stellenbosch, South Africa;
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EM Unit, Central Analytical Facilities, Stellenbosch University, Stellenbosch, South Africa;
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Adriana Bozzi
Adriana Bozzi
California Institute for Medical Research, San Jose, California;
Division of Cardiology, Department of Medicine, School of Medicine, Stanford University, Stanford, California;
School of Medicine, Cardiovascular Institute, Stanford University, Stanford, California;
Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil;
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Division of Cardiology, Department of Medicine, School of Medicine, Stanford University, Stanford, California;
School of Medicine, Cardiovascular Institute, Stanford University, Stanford, California;
Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil;
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Nazish Sayed
Nazish Sayed
Division of Cardiology, Department of Medicine, School of Medicine, Stanford University, Stanford, California;
School of Medicine, Cardiovascular Institute, Stanford University, Stanford, California;
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School of Medicine, Cardiovascular Institute, Stanford University, Stanford, California;
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Joseph C. Wu
Joseph C. Wu
Division of Cardiology, Department of Medicine, School of Medicine, Stanford University, Stanford, California;
School of Medicine, Cardiovascular Institute, Stanford University, Stanford, California;
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School of Medicine, Cardiovascular Institute, Stanford University, Stanford, California;
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David A. Stevens
David A. Stevens
California Institute for Medical Research, San Jose, California;
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California
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Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California
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Trypanosoma cruzi is the etiologic agent of Chagas disease (CD), which can result in severe cardiomyopathy. Trypanosoma cruzi is endemic to the Americas, and of particular importance in Latin America. In the United States and other non-endemic countries, rising case numbers have also been observed. The currently used drugs are benznidazole (BNZ) and nifurtimox, which have limited efficacy during chronic infection. We repurposed itraconazole (ICZ), originally an antifungal, in combination with amiodarone (AMD), an antiarrhythmic, with the goal of interfering with T. cruzi infection. Human pluripotent stem cells (hiPSCs) were differentiated into cardiomyocytes (hiPSC-CMs). Vero cells or hiPSC-CMs were infected with T. cruzi trypomastigotes of the II or I strain in the presence of ICZ and/or AMD. After 48 hours, cells were Giemsa stained, and infection and multiplication were evaluated microscopically. Trypanosoma cruzi infection and multiplication were evalutated also by electron microscopy. BNZ was used as a reference compound. Cell metabolism in the presence of test substances was assessed. Itraconazole and AMD showed strain- and dose-dependent interference with T. cruzi infection and multiplication in Vero cells or hiPSC-CMs. Combinations of ICZ and AMD were more effective against T. cruzi than the single substances, or BNZ, without affecting host cell metabolism, and better preserving host cell integrity during infection. Our in vitro data in hiPSC-CMs suggest that a combination of ICZ and AMD might serve as a treatment option for CD in patients, but that different responses due to T. cruzi strain differences have to be taken into account.
Author Notes
Disclosure: R. T. M. has a patent 14/990,031 pending.
Financial support: This work was supported by fundings from the National Institutes of Health (NIH) R01 HL141371, R01 HL141851 (J. C. W.), and NIH K01 HL135455 (N. S.).
Authors’ addresses: Gabriele Sass, California Institute for Medical Research, San Jose, CA, E-mail: gabriele.sass@cimr.org. Roy T. Madigan, Animal Hospital of Smithson Valley, Spring Branch, TX, E-mail: roytmadigan@yahoo.com. Lydia-Marie Joubert, Department of Microbiology, Stellenbosch University, Stellenbosch, South Africa, and EM Unit, Central Analytical Facilities, Stellenbosch University, Stellenbosch, South Africa, E-mail: lydiaj@sun.ac.za. Adriana Bozzi, California Institute for Medical Research, San Jose, CA, Division of Cardiology, Department of Medicine, School of Medicine, Stanford University, Stanford, CA, Institute of Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, and Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil, E-mail: adriana.bozzi@gmail.com. Nazish Sayed and Joseph C. Wu, Division of Cardiology, Department of Medicine, School of Medicine, Stanford University, Stanford, CA, and School of Medicine, Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, E-mails: sayedns@stanford.edu and joewu@stanford.edu. David A. Stevens, California Institute for Medical Research, San Jose, CA, and Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, E-mail: stevens@stanford.edu.
These authors contributed equally to this work.
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- Effects of AMD and ICZ on infection of Vero cells with T. cruzi strain TcII.
- Effects of AMD and ICZ on infection of hiPSC-CMs with TcII.
- Effects of AMD and ICZ on infection of hiPSC-CMs with TcI.
- Effects of ICZ, AMD, or their combinations on hiPSC-CM metabolism.
- Effects of ICZ, AMD, or their combinations on T. cruzi–infected hiPSC-CM cellular and amastigote structure.
- DISCUSSION
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1.
World Health Organization, 2015. Chagas disease in Latin America: an epidemiological update based on 2010 estimates. Wkly Epidemiol Rec 90: 33–44.
-
2.
Jurberg C, 2009. Chagas: one hundred years later. Bull World Health Organ 87: 491–492.
-
3.
Kirchhoff LV, 2011. Epidemiology of American trypanosomiasis (Chagas disease). Adv Parasitol 75: 1–18.
-
4.
Tanowitz HB, Kirchhoff LV, Simon D, Morris SA, Weiss LM, Wittner M, 1992. Chagas’ disease. Clin Microbiol Rev 5: 400–419.
-
5.
Bonney KM, 2014. Chagas disease in the 21st century: a public health success or an emerging threat? Parasite 21: 11.
-
6.
Bern C, Kjos S, Yabsley MJ, Montgomery SP, 2011. Trypanosoma cruzi and Chagas’ disease in the United States. Clin Microbiol Rev 24: 655–681.
-
7.
Bern C, Montgomery SP, 2009. An estimate of the burden of Chagas disease in the United States. Clin Infect Dis 49: e52–e54.
-
8.
Monteiro FA, Weirauch C, Felix M, Lazoski C, Abad-Franch F, 2018. Evolution, systematics, and biogeography of the triatominae, vectors of Chagas disease. Adv Parasitol 99: 265–344.
-
9.
Zingales B et al. 2012. The revised Trypanosoma cruzi subspecific nomenclature: rationale, epidemiological relevance and research applications. Infect Genet Evol 12: 240–253.
-
10.
Vago AR, Andrade LO, Leite AA, d’Avila Reis D, Macedo AM, Adad SJ, Tostes S Jr., Moreira MC, Filho GB, Pena SD, 2000. Genetic characterization of Trypanosoma cruzi directly from tissues of patients with chronic Chagas disease: differential distribution of genetic types into diverse organs. Am J Pathol 156: 1805–2189.
-
11.
Zingales B, 2018. Trypanosoma cruzi genetic diversity: something new for something known about Chagas disease manifestations, serodiagnosis and drug sensitivity. Acta Trop 184: 38–52 [Review].
-
12.
de Andrade AL, Zicker F, de Oliveira RM, Almeida Silva S, Luquetti A, Travassos LR, Almeida IC, de Andrade SS, de Andrade JG, Martelli CM, 1996. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet 348: 1407–1413.
-
13.
Fragata Filho AA, da Silva MA, Boainain E, 1995. Ethiologic treatment of acute and chronic Chagas’ Disease [corrected]. Sao Paulo Med J 113: 867–872.
-
14.
Urbina JA, 2010. Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches. Acta Trop 115: 55–68.
-
15.
Morillo CA et al. 2017. Benznidazole and posaconazole in eliminating parasites in asymptomatic T. cruzi carriers: the STOP-CHAGAS trial. J Am Coll Cardiol 69: 939–947.
-
16.
Assíria Fontes Martins T, de Figueiredo Diniz L, Mazzeti AL, da Silva do Nascimento ÁF, Caldas S, Caldas IS, de Andrade IM, Ribeiro I, Bahia MT, 2015. Benznidazole/itraconazole combination treatment enhances anti-Trypanosoma cruzi activity in experimental Chagas disease. PLoS One 10: e0128707.
-
17.
Paniz-Mondolfi AE, Pérez-Alvarez AM, Lanza G, Márquez E, Concepción JL, 2009. Amiodarone and itraconazole: a rational therapeutic approach for the treatment of chronic Chagas’ disease. Chemotherapy 55: 228–233.
-
18.
Churko JM, Burridge PW, Wu JC, 2013. Generation of human iPSCs from human peripheral blood mononuclear cells using non-integrative Sendai virus in chemically defined conditions. Methods Mol Biol 1036: 81–88.
-
19.
Lian X, Hsiao C, Wilson G, Zhu K, Hazeltine LB, Azarin SM, Raval KK, Zhang J, Kamp TJ, Palecek SP, 2012. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci USA 109: E1848–E1857.
-
20.
Andrade D et al. 2012. Trypanosoma cruzi invades host cells through the activation of endothelin and bradykinin receptors: a converging pathway leading to chagasic vasculopathy. Br J Pharmacol 165: 1333–1347.
-
21.
Burridge PW et al. 2014. Chemically defined generation of human cardiomyocytes. Nat Methods 11: 855–860.
-
22.
Bozzi A, Sayed N, Matsa E, Sass G, Neofytou E, Clemons KV, Correa-Oliveira R, Stevens DA, Wu JC, 2019. Using human induced pluripotent stem cell-derived cardiomyocytes as a model to study Trypanosoma cruzi infection. Stem Cell Reports pii: S2213–S6711(19)30139-0. doi: 10.1016/j.stemcr.2019.04.017 [Epub ahead of print].
-
23.
Scudiero DA, Shoemaker RH, Paull KD, Monks A, Tierney S, Nofziger TH, Currens MJ, Seniff D, Boyd MR, 1988. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res 48: 4827–4833.
-
24.
Coura JR, de Castro SL, 2002. A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz 97: 3–24.
-
25.
Molina I, Salvador F, Sánchez-Montalvá A, Artaza MA, Moreno R, Perin L, Esquisabel A, Pinto L, Pedraz JL, 2017. Pharmacokinetics of benznidazole in healthy volunteers and implications in future clinical trials. Antimicrob Agents Chemother 61: e01912–e01916.
-
26.
Perdomo VG, Rigalli JP, Luquita MG, Pellegrino JM, Ruiz ML, Catania VA, 2016. Up-regulation of ATP-binding cassette transporters in the THP-1 human macrophage cell line by the antichagasic benznidazole. Mem Inst Oswaldo Cruz 111: 707–711.
-
27.
Exeltis USA, Inc., 2017. Benznidazole Package Insert. Florham Park, NJ: Exeltis USA, Inc.
-
28.
Morillo CA et al. BENEFIT Investigators, 2015. Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. N Engl J Med 373: 1295–1306.
-
29.
Pecoul B et al. 2016. The BENEFIT Trial: where do we go from here? PLoS Negl Trop Dis 10: e0004343.
-
30.
Cancado JR, 2002. Long term evaluation of etiological treatment of Chagas disease with benznidazole. Rev Inst Med Trop Sao Paulo 44: 29–37.
-
31.
Apt W, 2010. Current and developing therapeutic agents in the treatment of Chagas disease. Drug Des Devel Ther 4: 243–253.
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