Distinct activities ofBartonella henselaetype IV secretion effector proteins modulate capillary-like sprout formation

Abstract

SummaryThe zoonotic pathogen Bartonella henselae (Bh) can lead to vasoproliferative tumour lesions in the skin and inner organs known as bacillary angiomatosis and bacillary peliosis. The knowledge on the molecular and cellular mechanisms involved in this pathogen-triggered angiogenic process is confined by the lack of a suitable animal model and a physiologically relevant cell culture model of angiogenesis. Here we employed a three-dimensional in vitro angiogenesis assay of collagen gel-embedded endothelial cell (EC) spheroids to study the angiogenic properties of Bh. Spheroids generated from Bh-infected ECs displayed a high capacity to form sprouts, which represent capillary-like projections into the collagen gel. The VirB/VirD4 type IV secretion system and a subset of its translocated Bartonella effector proteins (Beps) were found to profoundly modulate this Bh-induced sprouting activity. BepA, known to protect ECs from apoptosis, strongly promoted sprout formation. In contrast, BepG, triggering cytoskeletal rearrangements, potently inhibited sprouting. Hence, the here established in vitro model of Bartonellainduced angiogenesis revealed distinct and opposing activities of type IV secretion system effector proteins, which together with a VirB/VirD4-independent effect may control the angiogenic activity of Bh during chronic infection of the vasculature.

The BatR/BatS Two-Component Regulatory System Controls the Adaptive Response ofBartonella henselaeduring Human Endothelial Cell Infection

“…Specific attention has been paid to the BatR/BatS TCS and its role in the regulation of the VirB T4SS and its translocated effector proteins. The interaction of B. henselae with HEC has been extensively studied (14,15,17,19,46), and substantial progress has been achieved toward the understanding of the role of the VirB T4SS and its secreted Beps in the mediation of this interaction (41,44,45,49). However, the regulation mechanism(s) controlling the expression of these virulence factors and the global response of the bacteria during HEC interaction remain elusive.…”

Strategies of exploitation of mammalian reservoirs by Bartonella species

“…Internalisation of bartonellae via invasomes (characterised by the formation of a bacterial aggregate on the cell surface, which is subsequently engulfed and internalised by an actin-dependant mechanisms [26]) is dependent on three VirB/D4 effectors, BepC, BepG, and BepF [52,53]. BepA has been shown to inhibit endothelial cell apoptosis through upregulation of cAMP levels in the cytosol [49] and it also promotes capillary sprout formation in an endothelial spheroid infection model, whereas BepG inhibits such sprouting [54]. The functions of BepB, BepD and BepE are still to be elucidated.…”

Bartonella henselae engages inside-out and outside-in signaling by integrin β1 and talin1 during invasome-mediated bacterial uptake

“…The Bep proteins trigger all known VirB/D4-associated phenotypic changes of infected endothelial cells (ECs), including (1) inhibition of apoptosis, (2) activation of an NF-kB-dependent pro-inflammatory response, (3) capillary-like sprout formation of ECs embedded in a 3D matrix, and (4) bacterial invasion of ECs as well as epithelial cells by a unique cellular structure termed the invasome (Schmid et al, 2004;Schmid et al, 2006;Rhomberg et al, 2009;Scheidegger et al, 2009;Selbach et al, 2009). Invasome formation has been shown to depend on the translocation of BepG or the combination of BepC and BepF into the recipient cells Truttmann et al, 2011).…”