Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Bartonella–host-cell interactions and vascular tumour formation

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.


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

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.


  1. Dehio, C. Molecular and cellular basis of Bartonella pathogenesis. Annu. Rev. Microbiol. 58, 365–390 (2004).

    Article  CAS  Google Scholar 

  2. Dehio, C. Recent progress in understanding Bartonella-induced vascular proliferation. Curr. Opin. Microbiol. 6, 61–65 (2003).

    Article  CAS  Google Scholar 

  3. Bass, J. W., Vincent, J. M. & Person, D. A. The expanding spectrum of Bartonella infections: I. Bartonellosis and trench fever. Pediatr. Infect. Dis. J. 16, 2–10 (1997).

    Article  CAS  Google Scholar 

  4. Bass, J. W., Vincent, J. M. & Person, D. A. The expanding spectrum of Bartonella infections: II. Cat-scratch disease. Pediatr. Infect. Dis. J. 16, 163–179 (1997).

    Article  CAS  Google Scholar 

  5. Zhang, P. et al. A family of variably expressed outer-membrane proteins (Vomp) mediates adhesion and autoaggregation in Bartonella quintana. Proc. Natl Acad. Sci. USA 101, 13630–13635 (2004).

    Article  CAS  Google Scholar 

  6. Abbott, R. C. et al. Experimental and natural infection with Bartonella henselae in domestic cats. Comp. Immunol. Microbiol. Infect. Dis. 20, 41–51 (1997).

    Article  CAS  Google Scholar 

  7. Schulein, R. et al. Invasion and persistent intracellular colonization of erythrocytes. A unique parasitic strategy of the emerging pathogen Bartonella. J. Exp. Med. 193, 1077–1086 (2001).

    Article  CAS  Google Scholar 

  8. Koesling, J., Aebischer, T., Falch, C., Schulein, R. & Dehio, C. Cutting edge: antibody-mediated cessation of hemotropic infection by the intraerythrocytic mouse pathogen Bartonella grahamii. J. Immunol. 167, 11–14 (2001).

    Article  CAS  Google Scholar 

  9. Boulouis, H. J. et al. Kinetics of Bartonella birtlesii infection in experimentally infected mice and pathogenic effect on reproductive functions. Infect. Immun. 69, 5313–5317 (2001).

    Article  CAS  Google Scholar 

  10. Seubert, A., Schulein, R. & Dehio, C. Bacterial persistence within erythrocytes: a unique pathogenic strategy of Bartonella spp. Int. J. Med. Microbiol. 291, 555–560 (2002).

    Article  CAS  Google Scholar 

  11. Lax, A. J. & Thomas, W. How bacteria could cause cancer: one step at a time. Trends Microbiol. 10, 293–299 (2002).

    Article  CAS  Google Scholar 

  12. Hatakeyama, M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nature Rev. Cancer 4, 688–694 (2004).

    Article  CAS  Google Scholar 

  13. Kempf, V. A., Hitziger, N., Riess, T. & Autenrieth, I. B. Do plant and human pathogens have a common pathogenicity strategy? Trends Microbiol. 10, 269–275 (2002).

    Article  CAS  Google Scholar 

  14. Tappero, J. W. et al. The epidemiology of bacillary angiomatosis and bacillary peliosis. JAMA 269, 770–775 (1993).

    Article  CAS  Google Scholar 

  15. Slater, L. N., Welch, D. F. & Min, K. W. Rochalimaea henselae causes bacillary angiomatosis and peliosis hepatis. Arch. Intern. Med. 152, 602–606 (1992).

    Article  CAS  Google Scholar 

  16. Carmeliet, P. Angiogenesis in health and disease. Nature Med. 9, 653–660 (2003).

    Article  CAS  Google Scholar 

  17. Koehler, J. E. & Tappero, J. W. Bacillary angiomatosis and bacillary peliosis in patients infected with human immunodeficiency virus. Clin. Infect. Dis. 17, 612–624 (1993).

    Article  CAS  Google Scholar 

  18. Brouqui, P. & Raoult, D. Bartonella quintana invades and multiplies within endothelial cells in vitro and in vivo and forms intracellular blebs. Res. Microbiol. 147, 719–731 (1996).

    Article  CAS  Google Scholar 

  19. Dehio, C., Meyer, M., Berger, J., Schwarz, H. & Lanz, C. Interaction of Bartonella henselae with endothelial cells results in bacterial aggregation on the cell surface and the subsequent engulfment and internalisation of the bacterial aggregate by a unique structure, the invasome. J. Cell Sci. 110, 2141–2154 (1997).

    CAS  PubMed  Google Scholar 

  20. Verma, A., Davis, G. E. & Ihler, G. M. Infection of human endothelial cells with Bartonella bacilliformis is dependent on Rho and results in activation of Rho. Infect. Immun. 68, 5960–5969 (2000).

    Article  CAS  Google Scholar 

  21. Verma, A., Davis, G. E. & Ihler, G. M. Formation of stress fibres in human endothelial cells infected with Bartonella bacilliformis is associated with altered morphology, impaired migration and defects in cell morphogenesis. Cell. Microbiol. 3, 169–180 (2001).

    Article  CAS  Google Scholar 

  22. Verma, A. & Ihler, G. M. Activation of Rac, Cdc42 and other downstream signalling molecules by Bartonella bacilliformis during entry into human endothelial cells. Cell. Microbiol. 4, 557–569 (2002).

    Article  CAS  Google Scholar 

  23. Dramsi, S. & Cossart, P. Intracellular pathogens and the actin cytoskeleton. Annu. Rev. Cell Dev. Biol. 14, 137–166 (1998).

    Article  CAS  Google Scholar 

  24. Manders, S. M. Bacillary angiomatosis. Clin. Dermatol. 14, 295–299 (1996).

    Article  CAS  Google Scholar 

  25. Sansonetti, P. J. War and peace at mucosal surfaces. Nature Rev. Immunol. 4, 953–964 (2004).

    Article  CAS  Google Scholar 

  26. Cornelis, G. R. The Yersinia Ysc–Yop 'type III' weaponry. Nature Rev. Mol. Cell Biol. 3, 742–752 (2002).

    Article  CAS  Google Scholar 

  27. De Martin, R., Hoeth, M., Hofer-Warbinek, R. & Schmid, J. A. The transcription factor NF-κB and the regulation of vascular cell function. Arterioscler. Thromb. Vasc. Biol. 20, E83–88 (2000).

    CAS  PubMed  Google Scholar 

  28. Fuhrmann, O. et al. Bartonella henselae induces NF-κB-dependent upregulation of adhesion molecules in cultured human endothelial cells: possible role of outer membrane proteins as pathogenic factors. Infect. Immun. 69, 5088–5097 (2001).

    Article  CAS  Google Scholar 

  29. Schmid, M. C. et al. The VirB type IV secretion system of Bartonella henselae mediates invasion, proinflammatory activation and antiapoptotic protection of endothelial cells. Mol. Microbiol. 52, 81–92 (2004).

    Article  CAS  Google Scholar 

  30. Kirby, J. E. & Nekorchuk, D. M. Bartonella-associated endothelial proliferation depends on inhibition of apoptosis. Proc. Natl Acad. Sci. USA 99, 4656–4661 (2002).

    Article  CAS  Google Scholar 

  31. Joshi, S. G., Francis, C. W., Silverman, D. J. & Sahni, S. K. Nuclear factor κB protects against host cell apoptosis during infection by inhibiting activation of apical and effector caspases and maintaining mitochondrial integrity. Infect. Immun. 71, 4127–4136 (2003).

    Article  CAS  Google Scholar 

  32. Conley, T., Slater, L. & Hamilton, K. Rochalimaea species stimulate human endothelial cell proliferation and migration in vitro. J. Lab. Clin. Med. 124, 521–528 (1994).

    CAS  PubMed  Google Scholar 

  33. Garcia, F. U., Wojta, J., Broadley, K. N., Davidson, J. M. & Hoover, R. L. Bartonella bacilliformis stimulates endothelial cells in vitro and is angiogenic in vivo. Am. J. Pathol. 136, 1125–1135 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Garcia, F. U., Wojta, J. & Hoover, R. L. Interactions between live Bartonella bacilliformis and endothelial cells. J. Infect. Dis. 165, 1138–1141 (1992).

    Article  CAS  Google Scholar 

  35. Maeno, N. et al. Live Bartonella henselae enhances endothelial cell proliferation without direct contact. Microb. Pathog. 27, 419–427 (1999).

    Article  CAS  Google Scholar 

  36. Kirby, J. E. In vitro model of Bartonella henselae-induced angiogenesis. Infect. Immun. 72, 7315–7317 (2004).

    Article  CAS  Google Scholar 

  37. Torisu, H. et al. Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: possible involvement of TNFα and IL-1α. Int. J. Cancer. 85, 182–188 (2000).

    Article  CAS  Google Scholar 

  38. Kempf, V. A. et al. Activation of HIF-1 in bacillary angiomatosis: evidence for a role of HIF-1 in bacterial infections. Circulation 111, 1054–1062 (2005).

    Article  CAS  Google Scholar 

  39. Kempf, V. A. et al. Evidence of a leading role for VEGF in Bartonella henselae-induced endothelial cell proliferations. Cell. Microbiol. 3, 623–632 (2001).

    Article  CAS  Google Scholar 

  40. Resto-Ruiz, S. I. et al. Induction of a potential paracrine angiogenic loop between human THP-1 macrophages and human microvascular endothelial cells during Bartonella henselae infection. Infect. Immun. 70, 4564–4570 (2002).

    Article  CAS  Google Scholar 

  41. Riess, T. et al. Bartonella adhesin A mediates a proangiogenic host cell response. J. Exp. Med. 200, 1267–1278 (2004).

    Article  CAS  Google Scholar 

  42. Dehio, C. & Meyer, M. Maintenance of broad-host-range incompatibility group P and group Q plasmids and transposition of Tn5 in Bartonella henselae following conjugal plasmid transfer from Escherichia coli. J. Bacteriol. 179, 538–540 (1997).

    Article  CAS  Google Scholar 

  43. Dehio, M., Knorre, A., Lanz, C. & Dehio, C. Construction of versatile high-level expression vectors for Bartonella henselae and the use of green fluorescent protein as a new expression marker. Gene 215, 223–229 (1998).

    Article  CAS  Google Scholar 

  44. Schulein, R. & Dehio, C. The VirB/VirD4 type IV secretion system of Bartonella is essential for establishing intraerythrocytic infection. Mol. Microbiol. 46, 1053–1067 (2002).

    Article  CAS  Google Scholar 

  45. Battisti, J. M. & Minnick, M. F. Development of a system for genetic manipulation of Bartonella bacilliformis. Appl. Environ. Microbiol. 65, 3441–3448 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Seubert, A., Hiestand, R., de la Cruz, F. & Dehio, C. A bacterial conjugation machinery recruited for pathogenesis. Mol. Microbiol. 49, 1253–1266 (2003).

    Article  CAS  Google Scholar 

  47. Schulein, R. et al. A bipartite signal mediates the transfer of type IV secretion substrates of Bartonella henselae into human cells. Proc. Natl Acad. Sci. USA 102, 856–861 (2005).

    Article  CAS  Google Scholar 

  48. Coleman, S. A. & Minnick, M. F. Establishing a direct role for the Bartonella bacilliformis invasion-associated locus B (IalB) protein in human erythrocyte parasitism. Infect. Immun. 69, 4373–4381 (2001).

    Article  CAS  Google Scholar 

  49. Zahringer, U. et al. Structure and biological activity of the short-chain lipopolysaccharide from Bartonella henselae ATCC 49882T. J. Biol. Chem. 279, 21046–21054 (2004).

    Article  Google Scholar 

  50. Miller, S. I., Ernst, R. K. & Bader, M. W. LPS, TLR4 and infectious disease diversity. Nature Rev. Microbiol. 3, 36–46 (2005).

    Article  CAS  Google Scholar 

  51. Hoiczyk, E., Roggenkamp, A., Reichenbecher, M., Lupas, A. & Heesemann, J. Structure and sequence analysis of Yersinia YadA and Moraxella UspAs reveal a novel class of adhesins. EMBO J. 19, 5989–5999 (2000).

    Article  CAS  Google Scholar 

  52. Comanducci, M. et al. NadA, a novel vaccine candidate of Neisseria meningitidis. J. Exp. Med. 195, 1445–1454 (2002).

    Article  CAS  Google Scholar 

  53. Batterman, H. J., Peek, J. A., Loutit, J. S., Falkow, S. & Tompkins, L. S. Bartonella henselae and Bartonella quintana adherence to and entry into cultured human epithelial cells. Infect. Immun. 63, 4553–4556 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Heller, R. et al. Bartonella alsatica sp. nov., a new Bartonella species isolated from the blood of wild rabbits. Int. J. Syst. Bacteriol. 49, 283–288 (1999).

    Article  Google Scholar 

  55. Heller, R. et al. Bartonella tribocorum sp. nov., a new Bartonella species isolated from the blood of wild rats. Int. J. Syst. Bacteriol. 48, 1333–1339 (1998).

    Article  CAS  Google Scholar 

  56. Roggenkamp, A. et al. Molecular analysis of transport and oligomerization of the Yersinia enterocolitica adhesin YadA. J. Bacteriol. 185, 3735–3744 (2003).

    Article  CAS  Google Scholar 

  57. Nummelin, H. et al. The Yersinia adhesin YadA collagen-binding domain structure is a novel left-handed parallel β-roll. EMBO J. 23, 701–711 (2004).

    Article  CAS  Google Scholar 

  58. Alsmark, C. M. et al. The louse-borne human pathogen Bartonella quintana is a genomic derivative of the zoonotic agent Bartonella henselae. Proc. Natl Acad. Sci. USA 101, 9716–9721 (2004).

    Article  CAS  Google Scholar 

  59. Cascales, E. & Christie, P. J. The versatile bacterial type IV secretion systems. Nature Rev. Microbiol. 1, 137–149 (2003).

    Article  CAS  Google Scholar 

  60. Sweger, D. et al. Conservation of the 17-kilodalton antigen gene within the genus Bartonella. Clin. Diagn. Lab. Immunol. 7, 251–257 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Shamaei-Tousi, A., Cahill, R. & Frankel, G. Interaction between protein subunits of the type IV secretion system of Bartonella henselae. J. Bacteriol. 186, 4796–4801 (2004).

    Article  CAS  Google Scholar 

  62. Schröder, G. & Lanka, E. The mating pair formation system of conjugative plasmids — a versatile secretion machinery for transfer of proteins and DNA. Plasmid 54, 1–25 (2005).

    Article  Google Scholar 

  63. Schmiederer, M., Arcenas, R., Widen, R., Valkov, N. & Anderson, B. Intracellular induction of the Bartonella henselae virB operon by human endothelial cells. Infect. Immun. 69, 6495–6502 (2001).

    Article  CAS  Google Scholar 

  64. Odenbreit, S. et al. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287, 1497–1500 (2000).

    Article  CAS  Google Scholar 

  65. Dang, T. A., Zhou, X. R., Graf, B. & Christie, P. J. Dimerization of the Agrobacterium tumefaciens VirB4 ATPase and the effect of ATP-binding cassette mutations on the assembly and function of the T-DNA transporter. Mol. Microbiol. 32, 1239–1253 (1999).

    Article  CAS  Google Scholar 

  66. Minnick, M. F. & Anderson, B. E. Bartonella interactions with host cells. Subcell. Biochem. 33, 97–123 (2000).

    Article  CAS  Google Scholar 

  67. Mitchell, S. J. & Minnick, M. F. Characterization of a two-gene locus from Bartonella bacilliformis associated with the ability to invade human erythrocytes. Infect. Immun. 63, 1552–1562 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Koehler, J. et al. Isolation of rochalimeae species from cutaneous and osseous lesions of bacillary angiomatosis. N. Engl. J. Med. 327, 1625–1631 (1992).

    Article  CAS  Google Scholar 

  69. McCord, A. M., Burgess, A. W. O., Whaley, M. J. & Anderson B. E. Interaction of Bartonella henselae with endothelial cells promotes MCP-1 gene expression and protein production and triggers monocyte migration. Infect. Immun. (in the press).

  70. Sander, A., Infektiologie: Diagnostic, Therapie, Prophylaxe. Handbuch und Atlas für Klinik und Praxis. (ed Hofmann, F.) Ch. 1.19 (Ecomed, Landsberg, 1991).

Download references


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.

Author information

Authors and Affiliations


Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links



Agrobacterium tumefaciens

Bartonella henselae

Bartonella quintana

Bordetella pertussis

Chlamydia trachomatis

Escherichia coli

Helicobacter pylori

Legionella pneumophila

Neisseria meningitidis

CDC Infectious Disease Information


cat-scratch disease










Christoph Dehio's homepage



Capacity to stimulate the growth of blood vessels.


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).


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


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


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.


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


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.


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).


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.


Plasmid with unknown function.


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.


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


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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dehio, C. Bartonella–host-cell interactions and vascular tumour formation. Nat Rev Microbiol 3, 621–631 (2005).

Download citation

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing