Abstract
Chagas disease is a tropical parasitic disease caused by the protozoan Trypanosoma cruzi, which affects about ten million people in its endemic regions of Latin America. After the initial acute stage of infection, 60–80% of infected individuals remain asymptomatic for several years to a lifetime; however, the rest develop the debilitating symptomatic stage, which affects the nervous system, digestive system, and heart. The challenges of Chagas disease have become global due to immigration. Despite well-documented dietary changes accompanying immigration, as well as a transition to a western style diet in the Chagas endemic regions, the role of host metabolism in the pathogenesis of Chagas disease remains underexplored. We have previously used a mouse model to show that host diet is a key factor regulating cardiomyopathy in Chagas disease. In this study, we investigated the effect of a high-fat diet on liver morphology and physiology, lipid metabolism, immune signaling, energy homeostasis, and stress responses in the murine model of acute T. cruzi infection. Our results indicate that in T. cruzi-infected mice, diet differentially regulates several liver processes, including autophagy, a stress response mechanism, with corresponding implications for human Chagas disease patients.
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References
Bern C, Martin DL, Gilman RH (2011) Acute and congenital Chagas disease. Adv Parasitol 75:19–47. doi:10.1016/B978-0-12-385863-4
Bjørkøy G, Lamark T, Pankiv S, Øvervatn A, Brech A, Johansen T (2009) Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol 452:181–197. doi:10.1016/S0076-6879(08)03612-4
Bonney KM (2014) Chagas disease in the 21st century: a public health success or an emerging threat? Parasite 21:1–10. doi:10.1051/parasite/2014012
Brima W1, Eden DJ, Mehdi SF, Bravo M, Wiese MM, Stein J, Almonte V, Zhao D, Kurland I, Pessin JE, Zima T, Tanowitz HB, Weiss LM, Roth J, Nagajyothi F (2015) The brighter (and evolutionarily older) face of the metabolic syndrome: evidence from Trypanosoma cruzi infection in CD-1 mice. Diabetes Metab Res Rev 31:346–359. doi:10.1002/dmrr.2636
Busiello RA, Savarese S, Lombardi A (2015) Mitochondrial uncoupling proteins and energy metabolism. Front Physiol 6:1–7. doi:10.3389/fphys.2015.00036
Chakravarthy MV, Zhu Y, López M, Yin L, Wozniak DF, Coleman T, Hu Z, Wolfgang M, Vidal-Puig A, Lane MD, Semenkovich CF (2007) Brain fatty acid synthase activates PPARα to maintain energy homeostasis. J Clin Invest 117:2539–2552. doi:10.1172/JCI31183
Chu KY, O’Reilly L, Ramm G, Biden TJ (2015) High-fat diet increases autophagic flux in pancreatic beta cells in vivo and ex vivo in mice. Diabetologia 58:2074–2078. doi:10.1007/s00125-015-3665-x
Collier HO, Fulton JD, Innes JR (1942) The oedema of mice infected with Trypanosoma cruzi, and the accompanying pathological lesions. Ann Trop Med Parasitol 36:137–150. doi:10.1080/00034983.1942.11685149
Combs TP, Nagajyothi F, Mukherjee S, de Almeida CJ, Jelicks LA, Schubert W, Lin Y, Jayabalan DS, Zhao D, Braunstein VL, Landskroner-Eiger S, Cordero A, Factor SM, Weiss LM, Lisanti MP, Tanowitz HB, Scherer PE (2005) The adipocyte as an important target cell for Trypanosoma cruzi infection. J Biol Chem 280:24085–24094. doi:10.1074/jbc.M412802200
Cunha-Neto E, Rizzo LV, Albuquerque F, Abel L, Guilherme L, Bocchi E, Bacal F, Carrara D, Ianni B, Mady C, Kalil J (1998) Cytokine production profile of heart-infiltrating T cells in Chagas disease cardiomyopathy. Braz J Med Biol Res 1:133–137. doi:10.1590/S0100-879X1998000100018
Galluzzi L, Pietrocola F, Levine B, Kroemer G (2014) Metabolic control of autophagy. Cell 159:1263–1276. doi:10.1016/j.cell.2014.11.006
Grayson M (2010) Chagas disease. Nature 465:S3. doi:10.1038/465S3a
Gupta S, Wen JJ, Garg NJ (2009) Oxidative stress in Chagas disease. Interdiscip Perspect Infect Dis 2009:190354. doi:10.1155/2009/190354
Gupta S1, Silva TS, Osizugbo JE, Tucker L, Spratt HM, Garg NJ (2014) Serum-mediated activation of macrophages reflects TcVac2 vaccine efficacy against chagas disease. Infect Immun 82:1382–1389. doi:10.1128/IAI.01186-13
Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13:251–262. doi:10.1038/nrm3311
Hsu HC, Chen CY, Lee BC, Chen MF (2015) High-fat diet induces cardiomyocyte apoptosis via the inhibition of autophagy. Eur J Nutr. doi:10.1007/s00394-015-1034-7
Jensen-Urstad AP, Semenkovich CF (2012) Fatty acid synthase and liver triglyceride metabolism: housekeeper or messenger? Biochim Biophys Acta 1821:747–753. doi:10.1016/j.bbalip.2011.09. 017
Johndrow C, Nelson R, Tanowitz H, Weiss LM, Nagajyothi F (2014) Trypanosoma cruzi infection results in an increase in intracellular cholesterol. Microbes Infect 16:337–344. doi:10.1016/j.micinf.2014.01.001
Jump DB (2011) Fatty acid regulation of hepatic lipid metabolism. Curr Opin Clin Nutr Metab Care 14:115–120. doi:10.1097/MCO.0b013e328342991c
Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141. doi:10.1038/ncb2152
Liu Y, Palanivel R, Rai E, Park M, Gabor TV, Scheid MP, Xu A, Sweeney G (2015) Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high-fat diet feeding in mice. Diabetes 64:36–48. doi:10.2337/db14-0267
Mao Y, Yu F, Wang J, Guo C, Fan X (2016) Autophagy: a new target for nonalcoholic fatty liver disease therapy. Hepat Med 8:27–37. doi:10.2147/HMER.S98120
Matsuzawa-Nagata N, Takamura T, Ando H, Nakamura S, Kurita S, Misu H, Ota T, Yokoyama M, Honda M, Miyamoto K, Kaneko S (2008) Increased oxidative stress precedes the onset of high-fat diet–induced insulin resistance and obesity. Metabolism 57:1071–1077. doi:10.1016/j.metabol.2008.03.010
McGillicuddy FC, Chiquoine EH, Hinkle CC, Kim RJ, Shah R, Roche HM, Smyth EM, Reilly MP (2009) Interferon γ attenuates insulin signaling, lipid storage and differentiation in human adipocytes via activation of the JAK/STAT pathway. J Biol Chem 284:31936–31944. doi:10.1074/jbc.M109.061655
Nagajyothi F, Machado FS, Burleigh BA, Jelicks LA, Scherer PE, Mukherjee S, Lisanti MP, Weiss LM, Garg NJ, Tanowitz HB (2012) Mechanisms of Trypanosoma cruzi persistence in Chagas disease. Cell Microbiol 14:634–643. doi:10.1111/j.1462- 5822.2012.01764
Nagajyothi F, Weiss LM, Silver DL, Desruisseaux MS, Scherer PE, Herz J, Tanowitz HB (2011) Trypanosoma cruzi utilizes the host low density lipoprotein receptor in invasion. PLoS Negl Trop Dis 5:e953. doi:10.1371/journal.pntd.0000953
Nagajyothi F, Weiss LM, Zhao D, Koba W, Jelicks LA, Cui MH, Factor SM, Scherer PE, Tanowitz HB (2014) High fat diet modulates Trypanosoma cruzi infection associated myocarditis. PLoS Negl Trop Dis 8:e3118. doi:10.1371/ journal. pntd .0003118
Navarro-Yepes J, Burns M, Anandhan A, Khalimonchuk O, del Razo LM, Quintanilla-Vega B, Pappa A, Panayiotidis MI, Franco R (2014) Oxidative stress, redox signaling, and autophagy: cell death versus survival. Antioxid Redox Signal 21:66–85. doi:10.1089/ars.2014.5837
Nelson GJ (1962) The lipid composition of normal mouse liver. J Lipid Research 3:256–262
Nguyen P, Leray V, Diez M, Serisier S, Bloc’h JL, Siliart B, Dumon H (2008) Liver lipid metabolism. J Anim Physiol Anim Nutr 92:272–283. doi:10.1111/j.1439- 0396.2007.00752.x
O’Neill HM1, Holloway GP, Steinberg GR (2013) AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity. Mol Cell Endocrinol 366:135–151. doi:10.1016/j.mce.2012.06.019
Rodriguez-Guardado A, González ML, Rodriguez M, Flores-Chavez M, Boga JA, Gascon J (2015) Trypanosoma cruzi infection in a Spanish liver transplant recipient. Clin Microbiol Infect 21:687e1–687e3. doi:10.1016/j.cmi.2015.03.022
Russell RC, Yuan HX, Guan KL (2014) Autophagy regulation by nutrient signaling. Cell Res 24:42–57. doi:10.1038/cr.2013.166
Sardinha LR, Mosca T, Elias RM, do Nascimento RS, Gonçalves LA, Bucci DZ, Marinho CR, Penha-Gonçalves C, Lima MR, Álvarez JM (2010) The liver plays a major role in clearance and destruction of blood trypomastigotes in Trypanosoma cruzi chronically infected mice. PLoS Negl Trop Dis 4:e578. doi:10.1371/journal.pntd.0000578
Schneider J, Cuervo AM (2014) Liver autophagy: much more than just taking out the trash. Nat Rev Gastroenterol Hepatol 11:187–200. doi:10.1038/nrgastro.2013.211
Schrauwen P, Hesselink MK (2004) The role of uncoupling protein 3 in fatty acid metabolism: protection against lipotoxicity? Proc Nutr Soc 63:287–292. doi:10.1079/ PNS 2004336
Shikanai-Yasuda MA, Carvalho NB (2012) Oral transmission of Chagas disease. Clin Infect Dis 54:845–852. doi:10.1093/cid/cir956
Tang SW, Ducroux A, Jeang KT, Neuveut C (2012) Impact of cellular autophagy on viruses: insights from hepatitis B virus and human retroviruses. J Biomed Sci 19:1–11. doi:10.1186/1423-0127-19-92
Tanowitz HB, Kirchhoff LV, Simon D, Morris SA, Weiss LM, Wittner M (1992) Chagas disease. Clin Microbiol Rev 5:400–419. doi:10.1128/CMR.5.4.400
Tanowitz HB, Weiss LM, Montgomery SP (2011) Chagas disease has now gone global. PLoS Negl Trop Dis 5:e1136. doi:10.1371/journal.pntd.0001136
Teixeira MM, Gazzinelli RT, Silva JS (2002) Chemokines, inflammation and Trypanosoma cruzi infection. Trends Parasitol 18:262–265. doi:10.1016/S1471-4922(02)02283-3
Wen JJ, Nagajyothi F, Machado FS, Weiss LM, Scherer PE, Tanowitz HB, Garg NJ (2014) Markers of oxidative stress in adipose tissue during Trypanosoma cruzi infection. Parasitol Res 113:3159–3165. doi:10.1007/s00436-014-3977-7
Acknowledgements
We acknowledge Dazhi Zhao, Department of Pathology at Albert Einstein College of Medicine, NY, for the technical help. We thank Erika Shor at the Public Health Research Institute for a critical reading of the manuscript. We thank Dr. Joan Durbin, Professor of Pathology at Rutgers New Jersey Medical School for her suggestions on the histology slides. This study was supported by grants from the National Heart, Lung, and Blood Institute (National Institutes of Health HL-112099 and HL-122866) to Jyothi Nagajyothi.
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All animal experimental protocols were approved by the Institutional Animal Care and Use Committees (IACUC) of Albert Einstein College of Medicine (No. 20100204).
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Kezia Lizardo, Vanessa Almonte, and Calvin Law contributed equally to this article.
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Lizardo, K., Almonte, V., Law, C. et al. Diet regulates liver autophagy differentially in murine acute Trypanosoma cruzi infection. Parasitol Res 116, 711–723 (2017). https://doi.org/10.1007/s00436-016-5337-2
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DOI: https://doi.org/10.1007/s00436-016-5337-2