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Cholesterol  2013 

Leishmania major Self-Limited Infection Increases Blood Cholesterol and Promotes Atherosclerosis Development

DOI: 10.1155/2013/754580

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Abstract:

Leishmania major infection of resistant mice causes a self-limited lesion characterized by macrophage activation and a Th1 proinflammatory response. Atherosclerosis is an inflammatory disease involving hypercholesterolemia and macrophage activation. In this study, we evaluated the influence of L. major infection on the development of atherosclerosis using atherosclerosis-susceptible apolipoprotein E-deficient (apoE KO) mice. After 6 weeks of infection, apoE KO mice exhibited reduced footpad swelling and parasitemia similar to C57BL/6 controls, confirming that both strains are resistant to infection with L. major. L. major-infected mice had increased plasma cholesterol levels and reduced triacylglycerols. With regard to atherosclerosis, noninfected mice developed only fatty streak lesions, while the infected mice presented with advanced lesions containing a necrotic core and an abundant inflammatory infiltrate. CD36 expression was increased in the aortic valve of the infected mice, indicating increased macrophage activation. In conclusion, L. major infection, although localized and self-limited in resistant apoE KO mice, has a detrimental effect on the blood lipid profile, increases the inflammatory cell migration to atherosclerotic lesions, and promotes atherogenesis. These effects are consequences of the stimulation of the immune system by L. major, which promotes the inflammatory components of atherosclerosis, which are primarily the parasite-activated macrophages. 1. Introduction Leishmania major is a protozoan parasite transmitted by sandflies of the genus Lutzomyia that inject the promastigote form into the dermis of the host. Once injected, the parasite is rapidly enclosed by phagocytic cells and transforms into the replicative intracellular amastigote form [1]. In immunocompetent hosts, such as C57BL/6 mice, L. major infection is a self-contained cutaneous lesion that elicits a Th1 immune response. In infected mice, the immune cells (macrophages, dendritic cells, natural killer cells, and T cells) produce cytokines and bioactive molecules, such as IFN-γ, IL-12, and nitric oxide (NO), which act against the protozoan [1]. Atherosclerosis is a chronic inflammatory disease associated with a high level of total cholesterol and proatherogenic lipoproteins (VLDL, IDL, and LDL), a prothrombotic status, and a Th1-polarized immune response [2, 3]. Macrophage and endothelial cell activation by atypical lipoproteins and proinflammatory cytokines induces the production of adhesion molecules, cytokines and chemokines, and causes oxidative stress [4]. Among

References

[1]  J. Liese, U. Schleicher, and C. Bogdan, “The innate immune response against Leishmania parasites,” Immunobiology, vol. 213, no. 3-4, pp. 377–387, 2008.
[2]  G. K. Hansson, “Inflammatory mechanisms in atherosclerosis,” Journal of Thrombosis and Haemostasis, vol. 7, no. 1, pp. 328–331, 2009.
[3]  R. Ross, “Atherosclerosis—an inflammatory disease,” The New England Journal of Medicine, vol. 340, no. 2, pp. 115–126, 1999.
[4]  G. K. Hansson and P. Libby, “The immune response in atherosclerosis: a double-edged sword,” Nature Reviews Immunology, vol. 6, no. 7, pp. 508–519, 2006.
[5]  S. Kiechl, G. Egger, M. Mayr et al., “Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study,” Circulation, vol. 103, no. 8, pp. 1064–1070, 2001.
[6]  G. Noll, “Pathogenesis of atherosclerosis: a possible relation to infection,” Atherosclerosis, vol. 140, no. 1, pp. S3–S9, 1998.
[7]  F. F. Mussa, H. Chai, X. Wang, Q. Yao, A. B. Lumsden, and C. Chen, “Chlamydia pneumoniae and vascular disease: an update,” Journal of Vascular Surgery, vol. 43, no. 6, pp. 1301–1307, 2006.
[8]  L. J. Murray, K. B. Bamford, D. P. J. O'Reilly, E. E. McCrum, and A. E. Evans, “Helicobacter pylori infection: relation with cardiovascular risk factors, ischaemic heart disease, and social class,” British Heart Journal, vol. 74, no. 5, pp. 497–501, 1995.
[9]  M. S. Burnett, S. Durrani, E. Stabile et al., “Murine cytomegalovirus infection increases aortic expression of proatherosclerotic genes,” Circulation, vol. 109, no. 7, pp. 893–897, 2004.
[10]  M. J. Doenhoff, R. G. Stanley, K. Griffiths, and C. L. Jackson, “An anti-atherogenic effect of Schistosoma mansoni infections in mice associated with a parasite-induced lowering of blood total cholesterol,” Parasitology, vol. 125, no. 5, pp. 415–421, 2002.
[11]  L. R. Portugal, L. R. Fernandes, G. C. Cesar et al., “Infection with Toxoplasma gondii increases atherosclerotic lesion in ApoE-deficient mice,” Infection and Immunity, vol. 72, no. 6, pp. 3571–3576, 2004.
[12]  J. H. Meurman, M. Sanz, and S. J. Janket, “Oral health, atherosclerosis, and cardiovascular disease,” Critical Reviews in Oral Biology and Medicine, vol. 15, no. 6, pp. 403–413, 2004.
[13]  H. Zhang, L. M. Wu, and J. Wu, “Cross-talk between apolipoprotein E and cytokines,” Mediators of Inflammation, vol. 2011, Article ID 949072, 10 pages, 2011.
[14]  L. S. Capettini, S. F. Cortes, J. F. Silva, J. I. Alvarez-Leite, and V. S. Lemos, “Decreased production of nNOS-derived hydrogen peroxide contributes to endothelial dysfunction in atherosclerosis,” British Journal of Pharmacology, vol. 164, no. 6, pp. 1738–1748, 2011.
[15]  P. G. Reeves, F. H. Nielsen, and G. C. Fahey, “AIN-93 purified diets for laboratory rodents: final report of the american institute of nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet,” The Journal of Nutrition, vol. 123, no. 11, pp. 1939–1951, 1993.
[16]  L. Q. Vieira, M. Goldschmidt, M. Nashleanas, K. Pfeffer, T. Mak, and P. Scott, “Mice lacking the TNF receptor p55 fail to resolve lesions caused by infection with Leishmania major, but control parasite replication,” The Journal of Immunology, vol. 157, no. 2, pp. 827–835, 1996.
[17]  S. Fazio, V. R. Babaev, A. B. Murray et al., “Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4647–4652, 1997.
[18]  J. Folch, M. Lees, and S. G. H. Sloane, “A simple method for the isolation and purification of total lipides from animal tissues,” The Journal of biological chemistry, vol. 226, no. 1, pp. 497–509, 1957.
[19]  B. Paigen, A. Morrow, P. A. Holmes, D. Mitchell, and R. A. Williams, “Quantitative assessment of atherosclerotic lesions in mice,” Atherosclerosis, vol. 68, no. 3, pp. 231–240, 1987.
[20]  G. Anders, C. L. Eisenberger, F. Jonas, and C. L. Greenblatt, “Distinguishing Leishmania tropica and Leishmania major in the Middle East using the polymerase chain reaction with kinetoplast DNA-specific primers,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 96, supplement 1, pp. S87–S92, 2002.
[21]  A. T. Shamshiev, F. Ampenberger, B. Ernst, L. Rohrer, B. J. Marsland, and M. Kopf, “Dyslipidemia inhibits Toll-like receptor-induced activation of CD8α-negative dendritic cells and protective Th1 type immunity,” Journal of Experimental Medicine, vol. 204, no. 2, pp. 441–452, 2007.
[22]  H. C. Santiago, C. F. Oliveira, L. Santiago et al., “Involvement of the chemokine RANTES (CCL5) in resistance to experimental infection with Leishmania major,” Infection and Immunity, vol. 72, no. 8, pp. 4918–4923, 2004.
[23]  C. F. Oliveira, D. Manzoni-de-Almeida, P. S. Mello et al., et al., “Characterization of chronic cutaneous lesions from TNF-receptor-1-deficient mice infected by Leishmania major,” Clinical and Developmental Immunology, vol. 2012, Article ID 865708, 12 pages, 2012.
[24]  F. Benhnini, M. Chenik, D. Laouini, H. Louzir, P. A. Cazenave, and K. Dellagi, “Comparative evaluation of two vaccine candidates against experimental leishmaniasis due to Leishmania major infection in four inbred mouse strains,” Clinical and Vaccine Immunology, vol. 16, no. 11, pp. 1529–1537, 2009.
[25]  D. Sacks and N. Noben-Trauth, “The immunology of susceptibility and resistance to Leishmania major in mice,” Nature Reviews Immunology, vol. 2, no. 11, pp. 845–858, 2002.
[26]  X. Zhou, G. Paulsson, S. Stemme, and G. K. Hansson, “Hypercholesterolemia is associated with a T helper (Th) 1/Th2 switch of the autoimmune response in atherosclerotic apo E-knockout mice,” Journal of Clinical Investigation, vol. 101, no. 8, pp. 1717–1725, 1998.
[27]  G. R. Jansen, M. E. Zanetti, and C. F. Hutchison, “Stdies on lipogenesis in vivo. Effects of starvation andre-feeding, and studies on cholesterol synthesis,” Biochemical Journal, vol. 99, no. 2, pp. 333–340, 1966.
[28]  M. L. Ginger, M. C. Prescott, D. G. Reynolds, M. L. Chance, and J. L. Goad, “Utilization of leucine and acetate as carbon sources for sterol and fatty acid biosynthesis by old and new world Leishmania species, Endotrypanum monterogeii and Trypanosoma cruzi,” European Journal of Biochemistry, vol. 267, no. 9, pp. 2555–2566, 2000.
[29]  D. T. Hart and G. H. Coombs, “Leishmania mexicana: energy metabolism of amastigotes and promastigotes,” Experimental Parasitology, vol. 54, no. 3, pp. 397–409, 1982.
[30]  M. Rizzo and K. Berneis, “Low-density lipoprotein size and cardiovascular risk assessment,” QJM, vol. 99, no. 1, pp. 1–14, 2006.
[31]  E. Esteve, W. Ricart, and J. M. Fernández-Real, “Dyslipidemia and inflammation: an evolutionary conserved mechanism,” Clinical Nutrition, vol. 24, no. 1, pp. 16–31, 2005.
[32]  C. G. Nieto, R. Barrera, M. A. Habela et al., “Changes in the plasma concentrations of lipids and lipoprotein fractions in dogs infected with Leishmania infantum,” Veterinary Parasitology, vol. 44, no. 3-4, pp. 175–182, 1992.
[33]  G. K. Hansson, “Inflammation, atherosclerosis, and coronary artery disease,” The New England Journal of Medicine, vol. 352, no. 16, pp. 1685–1626, 2005.

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