Abstract
The Rickettsiales Ehrlichia ruminantium, the causal agent of the fatal tick-borne disease Heartwater, induces severe damage to the vascular endothelium in ruminants. Nevertheless, E. ruminantium-induced pathobiology remains largely unknown. Our work paves the way for understanding this phenomenon by using quantitative proteomic analyses (2D-DIGE-MS/MS, 1DE-nanoLC-MS/MS and biotin-nanoUPLC-MS/MS) of host bovine aorta endothelial cells (BAE) during the in vitro bacterium intracellular replication cycle. We detect 265 bacterial proteins (including virulence factors), at all time-points of the E. ruminantium replication cycle, highlighting a dynamic bacterium–host interaction. We show that E. ruminantium infection modulates the expression of 433 host proteins: 98 being over-expressed, 161 under-expressed, 140 detected only in infected BAE cells and 34 exclusively detected in non-infected cells. Cystoscape integrated data analysis shows that these proteins lead to major changes in host cell immune responses, host cell metabolism and vesicle trafficking, with a clear involvement of inflammation-related proteins in this process. Our findings led to the first model of E. ruminantium infection in host cells in vitro, and we highlight potential biomarkers of E. ruminantium infection in endothelial cells (such as ROCK1, TMEM16K, Albumin and PTPN1), which may be important to further combat Heartwater, namely by developing non-antibiotic-based strategies.
Highlights
Introduction published maps and institutional affilEhrlichia ruminantium is a Gram-negative, obligate intracellular bacterium that belongs to the Rickettsiales order
The set of selected differentially expressed proteins for each of the experimental group (E. ruminantium-infected vs. uninfected bovine aorta endothelial cells (BAE) cells, at different time-points post-infection) comparisons was used for Principal Component Analysis (PCA) (Supplementary Figure S2B)
Our study provides an integrated host and bacterial proteomics analysis of the infection of primary bovine endothelial cells with the etiologic agent of Heartwater, E. ruminantium
Summary
Ehrlichia ruminantium is a Gram-negative, obligate intracellular bacterium that belongs to the Rickettsiales order. It is transmitted by Amblyomma ticks and causes Heartwater, an acute and fatal disease of ruminants, present throughout sub-Saharan Africa and some islands in the Indian Ocean and the Caribbean (from where it threatens to invade the Americas) [1]. E. ruminantium is the only Ehrlichia sp. That mainly infects vascular endothelial cells, covering small- and medium-sized blood vessels in infected animals. E. ruminantium can be propagated experimentally by serial passages in culture in different cell types, but most reliably in finite culture of endothelial cells (as reviewed in [1]). E. ruminantium has a developmental cycle characterized by two distinct iations
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