Recent progress in understanding Bartonella-induced vascular proliferation

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Abstract

The ability to induce endothelial cell proliferation is a common feature of human pathogenic Bartonella species. Recent data have indicated that bartonellae can provoke angioproliferation by at least two independent mechanisms: directly, by triggering proliferation and inhibiting apoptosis of endothelial cells; and indirectly, by stimulating a paracrine angiogenic loop of vascular endothelial growth factor production by infected macrophages. A NF-κB-mediated acute inflammatory reaction of the Bartonella-infected endothelium appears to be critical for the recruitment of monocytes/macrophages and the initiation and maintenance of a paracrine angiogenic loop. Given that bartonellae effectively adhere to and invade endothelial cells, their ability to trigger angioproliferation might represent a dedicated pathogenic strategy for expanding the bacterial host cell habitat.

Introduction

Bartonellae are arthropod-borne, Gram-negative pathogens capable of causing long-lasting intraerythrocytic infections in their mammalian reservoirs and eventually diverse disease manifestations in incidentally infected mammalian hosts [1]. The genus Bartonella currently comprises 19 species, seven of which have been associated with human disease. The human-specific species Bartonella bacilliformis (Carrion’s disease: Oroya fever and verruga peruana) and B. quintana (trench fever, bacillary angiomatosis and endocarditis) and the zoonotic species B. henselae (cat scratch disease, bacillary angiomatosis and peliosis, endocarditis, bacteraemia with fever and neuroretinitis) are responsible for most human infections [2]. These three Bartonella species are also unique among all known bacterial pathogens in their ability to cause angiogenic lesions.

Angiogenesis is the process of forming new capillaries from pre-existing ones. Bartonella-triggered pathological angiogenesis typically manifests itself either as Kaposi’s sarcoma-like lesions of the skin, known as verruga peruana (B. bacilliformis) or bacillary angiomatosis (B. quintana and B. henselae), or as a cystic form in the liver and spleen, referred to as bacillary peliosis (primarily B. henselae). These lesions comprise proliferating endothelial cells, bacteria, and mixed infiltrates of macrophages/monocytes and polymorphonuclear neutrophils (PMNs) 3., 4.. Bartonellae are found as aggregates, surrounding and within endothelial cells, indicating that the endothelium represents a target tissue for intra- and extracellular colonisation in vivo [4].

The fascinating angioproliferative process of bartonellae has attracted considerable interest both as a basic and clinically important biological system, representing a paradigm for pathogen-triggered tumour formation. In this review, we cover the recent progress made in understanding Bartonella-stimulated angioproliferation, focusing on the best-understood model, B. henselae. Pathogen-induced tumour formation, as well as other aspects of the pathogenesis of bartonellae (i.e. their unique interaction with erythrocytes) have been extensively covered by several recent reviews 1., 5., 6., 7..

Section snippets

Colonisation of endothelial cells by Bartonella spp.

The colonisation of vascular endothelium is considered a crucial step in the establishment and maintenance of Bartonella-triggered angioproliferative lesions. Bartonellae are found in close association with proliferating endothelial cells and bacterial eradication by antibiotic treatment results in tumour regression [4].

Bacterial adhesion to and invasion of endothelial cells has primarily been studied in cultured human umbilical vein endothelial cells (HUVEC). Within several hours, all three

Direct mitotic stimulation of endothelial cells by Bartonella

Angiogenesis is a complex process involving several carefully orchestrated steps: proliferation and migration of endothelial cells, followed by their reorganisation into new capillaries. HUVEC and other cultured human endothelial cells have provided in vitro systems to study Bartonella-induced angioproliferation. Live B. bacilliformis, B. quintana and B. henselae, as well as cell-free extracts of these bacteria, are capable of stimulating the proliferation of HUVEC 14., 15.. B. henselae and B.

A paracrine loop of endothelial cell proliferation by VEGF released from Bartonella-infected macrophages

Cells of the mononuclear phagocyte lineage (i.e. macrophages) are capable of producing potent angiogenic factors upon activation [18]. Bacterial activation of the monocyte/macrophage infiltrate, typically found in bacillary angiomatosis lesions 3., 4., might result in the release of angiogenic substances and thereby contribute to the process of angioproliferation. Two independent reports 19.••, 20.•• support such a paracrine loop model for Bartonella-triggered angiogenesis.

Vascular endothelial

A Bartonella-triggered inflammatory reaction of endothelial cells may be required for initiating the paracrine angiogenic loop

The mixed infiltrate of macrophages/monocytes and neutrophils found in Bartonella-triggered angioproliferative lesions is indicative of chronic inflammation. An acute inflammatory reaction triggered by the Bartonella-infected endothelium may be crucial for initiating chronic inflammation. In general, an acute inflammatory response is thought to induce a mediator cascade that activates the endothelium, resulting in the release of proinflammatory chemoattractants and the sequential establishment

Bartonella-triggered inhibition of endothelial apoptosis

Cell death by apoptosis is a common response of mammalian cells to bacterial infection. However, some pathogens have also been found to alleviate or even to inhibit apoptosis 6., 27.. Likewise, B. henselae specifically inhibits apoptosis of HUVEC in vitro by suppressing both early and late events in apoptosis — namely caspase activation and DNA fragmentation, respectively [28••]. No direct cell contact is necessary for the antiapoptotic effect, suggesting a soluble bacterial factor. It was

Conclusions

Recent studies on the interaction of Bartonella with vascular endothelial cells have widened our understanding of the process of pathogen-triggered angioproliferation. Figure 1 summarises the emerging picture of this pathogenic process, which is likely to serve to extend the host cellular habitat of the pathogen. Bartonellae display a marked tropism towards vascular endothelial cells, resulting in bacterial adhesion and invasion. These bacterial interactions are directly accompanied by

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

I would like to thank C Thompson, A Seubert, M Schmid and I Carena for critical reading of this manuscript. Research in my laboratory is supported by grants from the Swiss National Science Foundation (3100-061777.00/1) and the Swiss Federal Office for Education and Science (00.0422-1) subsidised by the 5th EU-framework programme ‘Quality of Life’ (contract QLK2-2000-01536).

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