Eimeria bovis infection modulates endothelial host cell cholesterol metabolism for successful replication

Abstract

During first merogony Eimeria bovis forms large macromeronts in endothelial host cells containing >120 000 merozoites I. During multiplication, large amounts of cholesterol are indispensable for the enormous offspring membrane production. Cholesterol auxotrophy was proven for other apicomplexan parasites. Consequently they scavenge cholesterol from their host cell apparently in a parasite-specific manner. We here analyzed the influence of E. bovis infection on endothelial host cell cholesterol metabolism and found considerable differences to other coccidian parasites. Overall, free cholesterol significantly accumulated in E. bovis infected host cells. Furthermore, a striking increase of lipid droplet formation was observed within immature macromeronts. Artificial host cell lipid droplet enrichment significantly improved E. bovis merozoite I production confirming the key role of lipid droplet contents for optimal parasite proliferation. The transcription of several genes being involved in both, cholesterol de novo biosynthesis and low density lipoprotein-(LDL) mediated uptake, was significantly up-regulated at a time in infected cells suggesting a simultaneous exploitation of these two cholesterol acquisition pathways. E. bovis scavenges LDL-derived cholesterol apparently through significantly increased levels of surface LDL receptor abundance and LDL binding to infected cells. Consequently, LDL supplementation significantly improved parasite replication. The up-regulation of the oxidized LDL receptor 1 furthermore identified this scavenger receptor as a key molecule in parasite-triggered LDL uptake. Moreover, cellular cholesterol processing was altered in infected cells as indicated by up-regulation of cholesterol-25-hydroxylase and sterol O-acyltransferase. Overall, these results show that E. bovis considerably exploits the host cell cholesterol metabolism to guarantee its massive intracellular growth and replication.Electronic supplementary materialThe online version of this article (doi:10.1186/s13567-015-0230-z) contains supplementary material, which is available to authorized users.

A newly described strain of Eimeria arloingi (strain A) belongs to the phylogenetic group of ruminant-infecting pathogenic species, which replicate in host endothelial cells in vivo

“…A similar feature has also been suggested for the pathogenic species E. bovis and E. zuernii (Kawahara et al, 2010). It is intriguing to verify that despite the different host The phylogenetic proximity of E. arloingi and E. bovis may be in accordance with other common features of parasite-host cell interactions, such as the modulation of host cell-apoptosis (Lang et al, 2009), -cytoskeleton (Hermosilla et al, 2008) and -metabolism (Hamid et al, 2014;Hamid et al, 2015;Silva et al, 2015;Taubert et al, 2010) to guarantee successful macromeront formation.…”

“…For example, E. bovis depends on the host endothelial cell supply of energy and cellular building blocks for its massive offspring formation (Hamid et al, 2014;Hamid et al, 2015). Most notably for cholesterol and given that apicomplexan protozoa are considered as defective in de novo cholesterol biosynthesis (Coppens et al, 2000;Ehrenman et al, 2013;Taubert et al, 2010), this parasite appears to scavenge cholesterol via different pathways during macromeront formation (Hamid et al, 2015) for successful replication. Additionally, the downregulation of early host endothelial cell immune reactions in presence of E. arloingi (Silva et al, 2015), E. bovis (Taubert et al, 2006;Taubert et al, 2010) and also E. ninakohlyakimovae (Perez et al, 2015) was reported.…”

Changes to cholesterol trafficking in macrophages by Leishmania parasites infection

“…In addition, this outcome has been corroborated by studies using isotope‐resolved metabolomics, where amastigotes exhibited a glucose‐sparing metabolism associated with increased rates of beta‐oxidation (Saunders et al., ). Thus, these data together with the rising significance of endocytically low‐density lipoprotein (LDL)‐derived cholesterol during parasitic infections (Bansal, Bhatti, & Sehgal, ; Hamid et al., ; Johndrow, Nelson, Tanowitz, Weiss, & Nagajyothi, ) prompted our interest in lipid trafficking and metabolism in the host cell, and in the Leishmania ‐containing PV in particular.…”

“…Thus, these data together with the rising significance of endocytically low-density lipoprotein (LDL)-derived cholesterol during parasitic infections (Bansal, Bhatti, & Sehgal, 2005;Hamid et al, 2015;Johndrow, Nelson, Tanowitz, Weiss, & Nagajyothi, 2014) prompted our interest in lipid trafficking and metabolism in the host cell, and in the Leishmaniacontaining PV in particular.…”

Comparative transcriptomics and host-specific parasite gene expression profiles inform on drivers of proliferative kidney disease

“…LDLR-A proteins are crucial in receptor-mediated endocytosis of ligands, particularly cholesterol and acyglycerols. Many parasites are unable to produce cholesterol and are, therefore, dependent on host acquisition to fuel cell proliferation and differentiation 46,50 . Consequent alterations in host cholesterol homeostasis can lead to immune dysregulation and disease pathology.…”