Statin-induced chronic cholesterol depletion inhibits Leishmania donovani infection: Relevance of optimum host membrane cholesterol

Abstract

Leishmania are obligate intracellular protozoan parasites that invade and survive within host macrophages leading to leishmaniasis, a major cause of mortality and morbidity worldwide, particularly among economically weaker sections in tropical and subtropical regions. Visceral leishmaniasis is a potent disease caused by Leishmania donovani. The detailed mechanism of internalization of Leishmania is poorly understood. A basic step in the entry of Leishmania involves interaction of the parasite with the host plasma membrane. In this work, we have explored the effect of chronic metabolic cholesterol depletion using lovastatin on the entry and survival of Leishmania donovani in host macrophages. We show here that chronic cholesterol depletion of host macrophages results in reduction in the attachment of Leishmania promastigotes, along with a concomitant reduction in the intracellular amastigote load. These results assume further relevance since chronic cholesterol depletion is believed to mimic physiological cholesterol modulation. Interestingly, the reduction in the ability of Leishmania to enter host macrophages could be reversed upon metabolic replenishment of cholesterol. Importantly, enrichment of host membrane cholesterol resulted in reduction in the entry and survival of Leishmania in host macrophages. As a control, the binding of Escherichia coli to host macrophages remained invariant under these conditions, thereby implying specificity of cholesterol requirement for effective leishmanial infection. To the best of our knowledge, these results constitute the first comprehensive demonstration that an optimum content of host membrane cholesterol is necessary for leishmanial infection. Our results assume relevance in the context of developing novel therapeutic strategies targeting cholesterol-mediated leishmanial infection.

Atorvastatin: In-Vivo Synergy with Metronidazole as Anti-Blastocystis Therapy

“…Statins have been demonstrated as excellent repurposing candidates for treatment of cryptosporidiosis in vitro [ 34 ]. Recently, anti-leishmanial effectiveness of atorvastatin and lovastatin was reported through inhibition of HMG-CoA reductase enzyme [ 35 , 36 ]. This antiparasitic activity of atorvastatin was supported by Mirza et al [ 14 ] who described that statins could modulate or even cease the Blastocystis compromise of intestinal epithelium through inhibition of the isoprenylation process and induced activation of the ROCK pathway thus, blocking Blastocystis reorganization of the tight junction complex of intestinal epithelium and blocking the contravene of host epithelial permeability.…”

Lipid hijacking: A unifying theme in vector-borne diseases

“…Intracellular parasites may use membrane lipids and host membrane repair pathways to facilitate entry. Invading Leishmania and T. cruzi require membrane cholesterol similar to other intracellular pathogens ( Pucadyil et al, 2004 ; Fernandes et al, 2007 ; Kumar et al, 2016 ). However, unlike the alphaviruses, T. cruzi utilizes lipid rafts containing sphingolipids, cholesterol and the ganglioside GM1 for cellular entry ( Fernandes et al, 2007 ; Barrias et al, 2007 ; Hissa et al, 2012 ).…”

Host-Directed Drug Therapies for Neglected Tropical Diseases Caused by Protozoan Parasites

“…During L. donovani infection, this statin-dependent reduction in cholesterol levels resulted in decreased attachment of infectious promastigotes to macrophages, which is critical for parasite invasion. Consequently, macrophages treated with lovastatin had fewer intracellular amastigotes ( Kumar et al, 2016 ). Furthermore, topical application of simvastatin to ear and footpad lesions of L. major - infected BALB/c and C57BL/6 mice reduced lesion size as well as parasitic burdens in draining lymph nodes ( Parihar et al, 2016 ).…”