Leishmania majorSelf-Limited Infection Increases Blood Cholesterol and Promotes Atherosclerosis Development

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.

Changes to cholesterol trafficking in macrophages by Leishmania parasites infection

“…Finally, mouse models (Fernandes et al, 2013;Ghosh, Bose, Roy, & Bhattacharyya, 2013;Ghosh et al, 2012;Shamshiev et al, 2007) and epidemiological data (Ghosh et al, 2011;Lal et al, 2007;Soares et al, 2010) suggest a correlation between hypocholesterolemia and hypolipidemia and progression of the disease. However, the kinetics and mechanism (s) leading to alterations in cholesterol distribution in host cell membranes, its extent, and effect on its biosynthesis are still not understood.…”

“…Transcriptomic studies of the host cells showed that Leishmania infection modulated the expression of genes associated with cholesterol biosynthesis, uptake, and efflux (Osorio y Fortea et al., ; Rabhi et al., ). Finally, mouse models (Fernandes et al., ; Ghosh, Bose, Roy, & Bhattacharyya, ; Ghosh et al., ; Shamshiev et al., ) and epidemiological data (Ghosh et al., ; Lal et al., ; Soares et al., ) suggest a correlation between hypocholesterolemia and hypolipidemia and progression of the disease. However, the kinetics and mechanism (s) leading to alterations in cholesterol distribution in host cell membranes, its extent, and effect on its biosynthesis are still not understood.…”

NCF2, MYO1F, S1PR4, and FCN1 as potential noninvasive diagnostic biomarkers in patients with obstructive coronary artery: A weighted gene co‐expression network analysis

“…GSEA analysis also revealed that patients with obstructive CAD with higher expression levels of NCF2, MYO1F, S1PR4, and FCN1 in PBMC showed enriched pathways in viral myocarditis, Leishmania infection, type I diabetes mellitus, and hematopoietic cell lineage. These pathways are critical for the development of atherosclerosis and CADs . Since more than 65% of STEMI patients suffer from obstructive CAD, it is presumable that this four‐gene signature could also be developed as a potential prognostic biomarker of obstructive CAD occurrence in STEMI patients.…”

“…These pathways are critical for the development of atherosclerosis and CADs. [25][26][27] Since more than 65% of STEMI patients suffer from obstructive CAD, 23,24 it is presumable that this four-gene signature could also be developed as a potential prognostic biomarker of obstructive CAD occurrence in STEMI patients. However, this warrants another separate study in the future.…”

Growth Performance, Metabolic Efficiency and Nutrient Utilization of BALB/C Mice Infected with Leishmania major Fed with Standard Rat Pellets or Annonaceae Fruit Pulp Pellets

“…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 parasiteactivated macrophages [35]. Several studies suggest that pathogenic bacteria, viruses and protozoa, contribute to the atherogenesis process [36,37,38,39,40].…”