Abstract
Apicomplexan parasites are well-known to modulate their host cells at diverse functional levels. As such, apicomplexan-induced alteration of host cellular cell cycle was described and appeared dependent on both, parasite species and host cell type. As a striking evidence of species-specific reactions, we here show that Eimeria bovis drives primary bovine umbilical vein endothelial cells (BUVECs) into a senescence-like phenotype during merogony I. In line with senescence characteristics, E. bovis induces a phenotypic change in host cell nuclei being characterized by nucleolar fusion and heterochromatin-enriched peripheries. By fibrillarin staining we confirm nucleoli sizes to be increased and their number per nucleus to be reduced in E. bovis-infected BUVECs. Additionally, nuclei of E. bovis-infected BUVECs showed enhanced signals for HH3K9me2 as heterochromatin marker thereby indicating an infection-induced change in heterochromatin transition. Furthermore, E. bovis-infected BUVECs show an enhanced β-galactosidase activity, which is a well-known marker of senescence. Referring to cell cycle progression, protein abundance profiles in E. bovis-infected endothelial cells revealed an up-regulation of cyclin E1 thereby indicating a cell cycle arrest at G1/S transition, signifying a senescence key feature. Similarly, abundance of G2 phase-specific cyclin B1 was found to be downregulated at the late phase of macromeront formation. Overall, these data indicate that the slow proliferative intracellular parasite E. bovis drives its host endothelial cells in a senescence-like status. So far, it remains to be elucidated whether this phenomenon indeed reflects an intentionally induced mechanism to profit from host cell-derived energy and metabolites present in a non-dividing cellular status.
Highlights
Eimeria spp. are widespread enteropathogens of domestic and wild vertebrates which usually cause mild pathology in affected intestine thereby resulting in either subclinical or mild clinical eimeriosis
In primary bovine umbilical vein endothelial cells (BUVECs), we recently reported on T. gondii-triggered G2/M arrest being accompanied by chromosome missegregation, the formation of supernumerary centrosomes and cytokinesis impairment (Velásquez et al, 2019)
When calculating the ratio of HH3K9me2 signals to nuclear area, we could confirm a significantly increased abundance of heterochromatin at single nucleus level for E. bovis-infected BUVECs during first merogony (E. bovis-infected BUVECs vs control cells: 4–22 days p.i.; all Ps ≤ 0.0001; Fig. 4F)
Summary
Eimeria spp. are widespread enteropathogens of domestic and wild vertebrates which usually cause mild pathology in affected intestine thereby resulting in either subclinical or mild clinical eimeriosis (coccidiosis). It has been described that E. bovis modulates the host cell cytoskeleton (Hermosilla et al, 2008a), inhibits host cell apoptosis (Lang et al, 2009), alters immunomodulatory molecule gene expression (Hermosilla et al, 2006; Taubert et al, 2006), influences nuclear factor-κB activation (Alcala-Canto and Ibarra-Velarde, 2008) and exploits host cellular cholesterol metabolism (Hamid et al, 2014, 2015; Taubert et al, 2010, 2018) This overall behaviour is in line with several other intracellular parasites which are well-known to modulate their host cell for successful intracellular development and proliferation. Pathogens from different parasite classes, such as Toxoplasma gondii, Leishmania spp., Trypanosoma cruzi and Encephalitozoon spp., induce cell cycle arrest and dampen
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