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Bartonella–host-cell interactions and vascular tumour formation

Nature Reviews Microbiology volume 3, pages 621–631 (2005)Cite this article

Key Points

  • The bartonellae infect erythrocytes in their mammalian reservoir host(s), which include humans, cats and ruminants, causing a long-lasting intra-erythrocytic bacteraemia. For these Gram-negative facultative intracellular pathogens, endothelial cells are also an important target cell, not just in reservoir hosts but in all mammals, including incidental human hosts in which there is no subsequent erythrocyte infection.

  • The bartonellae have pleiotropic effects on human endothelial cells, the result of which can be the stimulation of vasoproliferation and subsequent vascular tumour formation.

  • The lack of a suitable animal model has hampered the elucidation of the molecular mechanisms that are responsible for Bartonella-triggered vascular tumour formation in vivo. However, in vitro cell-culture studies using human umbilical-vein endothelial cells have identified several key steps. These include vascular colonization by conventional phagocytosis and also by the engulfment of a 'clump' of bacteria through a mechanism that requires massive actin rearrangements and forms a structure known as an invasome; and activation of the transcription factor NF-κB. NF-κB activation not only mediates the inflammatory response, which may allow the stimulation of further vasoproliferation through the secretion of pro-angiogenic factors by the infiltrating monocytes and lymphocytes, but might also confer protection from apoptosis. In addition, mitogenic stimulation of endothelial cells can occur indirectly, in a paracrine manner.

  • The advent of molecular genetic analysis techniques for use in the bartonellae has led to the identification of a number of virulence factors. These include the non-fimbrial adhesins Bartonella adhesin A (BadA) and variably expressed outer-membrane proteins A–D (VompA–D), as well as the two type IV secretion systems, Trw and VirB/D4, and the seven VirB/D4-secreted effectors BepA–G.

Abstract

Bartonellae are arthropod-borne bacterial pathogens that typically cause persistent infection of erythrocytes and endothelial cells in their mammalian hosts. In human infection, these host-cell interactions result in a broad range of clinical manifestations. Most remarkably, bartonellae can trigger massive proliferation of endothelial cells, leading to vascular tumour formation. The recent availability of infection models and bacterial molecular genetic techniques has fostered research on the pathogenesis of the bartonellae and has advanced our understanding of the virulence mechanisms that underlie the host-cell tropism, the subversion of host-cell functions during bacterial persistence, as well as the formation of vascular tumours by these intriguing pathogens.

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Figure 1: Bartonella henselae infection.
Figure 2: Model of the course of Bartonella tribocorum infection in the mammalian reservoir host.
Figure 3: Model of Bartonella-triggered vascular tumour formation.
Figure 4: Bartonella adhesin A (BadA)-like non-fimbrial adhesins.
Figure 5: Bartonella VirB/VirD4 and Beps.
Figure 6: Bartonella-translocated effector proteins (Beps) subvert endothelial cell function.

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Acknowledgements

I thank Dr G. Schröder and H. L. Saenz for helpful comments on this manuscript. Research in my laboratory is funded by a grant from the Swiss National Science Foundation.

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  1. Division of Molecular Microbiology, Biozentrum, University of Basel, Klingelbergstrasse 70, Basel, CH-4056, Switzerland

    Christoph Dehio

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DATABASES

Entrez

Agrobacterium tumefaciens

Bartonella henselae

Bartonella quintana

Bordetella pertussis

Chlamydia trachomatis

Escherichia coli

Helicobacter pylori

Legionella pneumophila

Neisseria meningitidis

CDC Infectious Disease Information

AIDS

cat-scratch disease

SwissProt

CD11

CD18

E-selectin

HIF-1

ICAM-1

IL-8

VEGF

FURTHER INFORMATION

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Glossary

VASOPROLIFERATIVE

Capacity to stimulate the growth of blood vessels.

NF-κB

A family of transcription factors important for proinflammatory and anti-apoptotic responses. They are activated by the phosphorylation and subsequent proteolytic degradation of the inhibitor molecule of κB (IκB).

PARACRINE

Form of signalling in which the target cell is close to the signal-releasing cell.

HYPOXIA

Reduction of the oxygen supply to a tissue to below physiological levels.

LIPID A

Component of lipopolysaccharide (LPS) that anchors the molecule to the cell surface by insertion into the outer membrane. The lipid A moiety is responsible for the endotoxic activity of LPS.

EXTRACELLULAR MATRIX

Secreted products of many different cell types that form an organized scaffold for cell support. Components of the extracellular matrix include collagen and laminin.

TYPE IV-LIKE PILUS

An elongated hair-like structure extending from the surface of Gram-negative cells that is independent of flagella, and which can retract and pull the cell forward.

CONJUGATION SYSTEM

System that mediates the transfer of DNA between bacterial cells after cell–cell contact. Conjugation is mediated by mobile genetic elements (usually plasmids or transposons), and is unidirectional and conservative (a copy of the DNA remains in the donor strain).

T-DNA

A DNA segment of the tumour-inducing (Ti) plasmid of Agrobacterium tumefaciens that is transferred into the nucleus of infected plant cells, where it is then stably integrated into the host genome and transcribed, causing crown gall disease.

CRYPTIC PLASMID

Plasmid with unknown function.

YEAST TWO-HYBRID INTERACTION ASSAY

Assay in which one protein is fused to a transcriptional activation domain and the other to a DNA-binding domain, and both fusion proteins are introduced into yeast. Expression of a reporter gene with the appropriate DNA-binding sites upstream of the promoter indicates that the two proteins interact physically.

PATHOGENICITY ISLAND

A contiguous block of genes acquired by horizontal transfer in which at least a subset of the genes code for virulence factors.

PARALOGUES

Homologous genes in the same organism that have evolved from a gene duplication and a subsequent divergence of function.

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Dehio, C. Bartonella–host-cell interactions and vascular tumour formation. Nat Rev Microbiol 3, 621–631 (2005). https://doi.org/10.1038/nrmicro1209

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