BACKGROUND: Infection with Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, results in chronic infection that leads to cardiomyopathy with increased mortality and morbidity in endemic regions. In a companion study, our group found that a high-fat diet (HFD) protected mice from T. cruzi-induced myocardial damage and significantly reduced post-infection mortality during acute T. cruzi infection. METHODS: In the present study metabolic syndrome was induced prior to T. cruzi infection by feeding a high fat diet. Also, mice were treated with anti-diabetic drug metformin. RESULTS: In the present study, the lethality of T. cruzi (Brazil strain) infection in CD-1 mice was reduced from 55% to 20% by an 8-week pre-feeding of an HFD to induce obesity and metabolic syndrome. The addition of metformin reduced mortality to 3%. CONCLUSIONS: It is an interesting observation that both the high fat diet and the metformin, which are known to differentially attenuate host metabolism, effectively modified mortality in T. cruzi-infected mice. In humans, the metabolic syndrome, as presently construed, produces immune activation and metabolic alterations that promote complications of obesity and diseases of later life, such as myocardial infarction, stroke, diabetes, Alzheimer's disease and cancer. Using an evolutionary approach, we hypothesized that for millions of years, the channeling of host resources into immune defences starting early in life ameliorated the effects of infectious diseases, especially chronic infections, such as tuberculosis and Chagas disease. In economically developed countries in recent times, with control of the common devastating infections, epidemic obesity and lengthening of lifespan, the dwindling benefits of the immune activation in the first half of life have been overshadowed by the explosion of the syndrome's negative effects in later life.

Charles University Prague Czech Republic

Department of Medicine Albert Einstein College of Medicine Bronx NY

Hofstra North Shore LIJ School of Medicine North Shore Long Island Jewish Health System Hempstead NY

James J Peters VA Medical Center Mount Sinai Medical Center Health System Bronx NY

Laboratory of Diabetes and Diabetes Related Research Feinstein Institute for Medical Research North Shore Long Island Jewish Health System Manhasset NY

Diabetes Metab Res Rev. 2015 May;31(4):344-5. doi: 10.1002/dmrr.2635. PubMed

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Ribeiro AL, et al. Diagnosis and management of Chagas disease and cardiomyopathy. Nat Rev Cardiol. 2012;9(10):576–89. PubMed

Tanowitz HB, Weiss LM, Montgomery SP. Chagas disease has now gone global. PLoS Negl Trop Dis. 2011;5(4):e1136. PubMed PMC

Nagajyothi F, et al. High fat diet modulates Trypanosoma cruzi infection associated myocarditis. PLoS Negl Trop Dis. 2014;8(10):e3118. PubMed PMC

Grundy SM, et al. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109(3):433–8. PubMed

Sarafidis PA, Nilsson PM. The metabolic syndrome: a glance at its history. J Hypertens. 2006;24(4):621–6. PubMed

Roth J. Evolutionary speculation about tuberculosis and the metabolic and inflammatory processes of obesity. Jama. 2009;301(24):2586–8. PubMed

Roth J, Szulc AL, Danoff A. Energy, evolution, and human diseases: an overview. Am J Clin Nutr. 2011;93(4):875s–83. PubMed

Singanayagam A, Singanayagam A, Chalmers JD. Obesity is associated with improved survival in community-acquired pneumonia. Eur Respir J. 2013;42(1):180–7. PubMed

Robert V, et al. Malaria and obesity: obese mice are resistant to cerebral malaria. Malar J. 2008;7:81. PubMed PMC

Beleigoli AM, et al. The “obesity paradox” in an elderly population with a high prevalence of Chagas disease: the 10-year follow-up of the Bambui (Brazil) Cohort Study of Aging. Int J Cardiol. 2013;166(2):523–6. PubMed

Leung CC, et al. Lower risk of tuberculosis in obesity. Arch Intern Med. 2007;167(12):1297–304. PubMed

Hassan GS, et al. Trypanosoma cruzi infection induces proliferation of vascular smooth muscle cells. Infect Immun. 2006;74(1):152–9. PubMed PMC

Nagajyothi F, et al. Alterations in glucose homeostasis in a murine model of Chagas disease. Am J Pathol. 2013;182(3):886–94. PubMed PMC

Nagajyothi F, et al. Curcumin treatment provides protection against Trypanosoma cruzi infection. Parasitol Res. 2012;110(6):2491–9. PubMed PMC

Morris SA, et al. Verapamil ameliorates clinical, pathologic and biochemical manifestations of experimental chagasic cardiomyopathy in mice. J Am Coll Cardiol. 1989;14(3):782–9. PubMed

Ishida Y. Fine structure of primary reticulum cell sacroma of the brain. Acta Neuropathol Suppl. 1975;(Suppl 6):147–53. PubMed

Johndrow C, et al. Trypanosoma cruzi infection results in an increase in intracellular cholesterol. Microbes Infect. 2014;16(4):337–44. PubMed PMC

Nagajyothi F, et al. Response of adipose tissue to early infection with Trypanosoma cruzi (Brazil strain). J Infect Dis. 2012;205(5):830–40. PubMed PMC

Nagajyothi F, et al. Mechanisms of Trypanosoma cruzi persistence in Chagas disease. Cell Microbiol. 2012;14(5):634–43. PubMed PMC

Nagajyothi F, et al. Trypanosoma cruzi infection of cultured adipocytes results in an inflammatory phenotype. Obesity (Silver Spring) 2008;16(9):1992–7. PubMed PMC

Combs TP, et al. The adipocyte as an important target cell for Trypanosoma cruzi infection. J Biol Chem. 2005;280(25):24085–94. PubMed

Basso B, et al. Acute Trypanosoma cruzi infection: IL-12, IL-18, TNF, sTNFR and NO in T. rangelivaccinated mice. Vaccine. 2004;22(15-16):1868–72. PubMed

Zhang L, Tarleton RL. Characterization of cytokine production in murine Trypanosoma cruzi infection by in situ immunocytochemistry: lack of association between susceptibility and type 2 cytokine production. Eur J Immunol. 1996;26(1):102–9. PubMed

Antunez MI, Cardoni RL. IL-12 and IFN-gamma production, and NK cell activity, in acute and chronic experimental Trypanosoma cruzi infections. Immunol Lett. 2000;71(2):103–9. PubMed

Rodrigues AA, et al. IFN-gamma plays a unique role in protection against low virulent Trypanosoma cruzi strain. PLoS Negl Trop Dis. 2012;6(4):e1598. PubMed PMC

Bartolomucci A, et al. Metabolic consequences and vulnerability to diet-induced obesity in male mice under chronic social stress. PLoS One. 2009;4(1):e4331. PubMed PMC

Shi H, et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116(11):3015–25. PubMed PMC

Faggioni R, Feingold KR, Grunfeld C. Leptin regulation of the immune response and the immunodeficiency of malnutrition. Faseb j. 2001;15(14):2565–71. PubMed

Nagajyothi F, et al. Crucial role of the central leptin receptor in murine Trypanosoma cruzi (Brazil strain) infection. J Infect Dis. 2010;202(7):1104–13. PubMed PMC

Holscher C, et al. Tumor necrosis factor alpha-mediated toxic shock in Trypanosoma cruzi-infected interleukin 10-deficient mice. Infect Immun. 2000;68(7):4075–83. PubMed PMC

Wen JJ, et al. Markers of oxidative stress in adipose tissue during Trypanosoma cruzi infection. Parasitol Res. 2014;113(9):3159–65. PubMed PMC

Nagajyothi F, et al. Trypanosoma cruzi utilizes the host low density lipoprotein receptor in invasion. PLoS Negl Trop Dis. 2011;5(2):e953. PubMed PMC

Brown MS, Goldstein JL. Regulation of the activity of the low density lipoprotein receptor in human fibroblasts. Cell. 1975;6(3):307–16. PubMed

Nath N, et al. Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J Immunol. 2009;182(12):8005–14. PubMed PMC

Lu B, et al. JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation. Proc Natl Acad Sci U S A. 2014;111(8):3068–73. PubMed PMC

Tsoyi K, et al. Metformin inhibits HMGB1 release in LPS-treated RAW 264.7 cells and increases survival rate of endotoxaemic mice. Br J Pharmacol. 2011;162(7):1498–508. PubMed PMC

Zhang T, et al. Metformin protects against hyperglycemia-induced cardiomyocytes injury by inhibiting the expressions of receptor for advanced glycation end products and high mobility group box 1 protein. Mol Biol Rep. 2014;41(3):1335–40. PubMed

Yao D, Brownlee M. Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes. 2010;59(1):249–55. PubMed PMC

Nishikawa T, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404(6779):787–90. PubMed

Andrews M, Soto N, Arredondo M. [Effect of metformin on the expression of tumor necrosis factor-alpha, Toll like receptors 2/4 and C reactive protein in obese type-2 diabetic patients]. Rev Med Chil. 2012;140(11):1377–82. PubMed