Bartonella henselae & HIF-1



Arbeitsgruppe Prof. Dr. med. Volkhard A. J. Kempf
e-mail: volkhard.kempf(at)kgu.de





 

Bartonella henselae

Bartonella henselae, the agent of cat-scratch disease in immunocompetent individuals, is a fastidious facultative intracellular, gram-negative pathogen. It is also the causal agent of bacillary angiomatosis and bacillary peliosis, which are histologically characterized as lobulated proliferation of endothelial cells in immunocompromised patients (e.g. AIDS).

Endothelial cells are one presumed habit at of Bartonella spp.The ability to induce vasculoproliferative disorders in humans is a unique feature of Bartonella spp., however the underlying molecular mechanisms need to be further elucidated. Parts of our current projects are described below; our research is funded by the Deutsche Forschungsgemeinschaft (SFB 766 and priotity research programs 1130, 1131, 1316).

Vasculoproliferative factors in Bartonella infections

The research group 'Bartonella' is investigating host cell-interactions mainly of Bartonella henselae. A novel 'two-step' model of pathogenicity has been described suggesting that host cell-derived vasculoproliferative factors play a crucial role in the pathogenesis of bacillary angiomatosis ("paracrine-loop model"). The resulting proliferation of endothelial cells could be interpreted as bacterial pathogens triggering the promotion of their own habitat: the host cell. Similar disease mechanisms are well known in the plant pathogen Agrobacterium tumefaciens which causes crown gall disease.
This fascinating angiogenic potential is of particular interest in terms of analysing bacteria-triggered tumour formation. Solid-tumour growth in animals and plants depends on the formation of a sophisticated vascular network consisting of blood vessels or water-conducting elements, respectively. The elucidation of tumourous diseases caused by bacteria might provide new insights into microbial pathogenicity, tumour growth and pathological angiogenesis. Moreover, the idea of the induction of a complete neoangiogenic process by a bacterium or its recombinant products is a fascinating concept in terms of the development of novel treatment strategies of ischemic disorders such as artherosclerosis.

Trimeric autotransporter adhesins (TAA)

We identified a nonfimbrial adhesin of B. henselae designated as Bartonella adhesin A (BadA). BadA is a 340-kD outer membrane protein, has a trimeric structure and contains domains homologous to the Yersinia enterocolitica adhesin A (YadA) and to the Xanthomonas adhesin-like protein A (XadA) of the plant pathogen Xanthomonas oryzae pv. oryzae.

Together these TAAs belong to the recently described family of trimeric autotransporter adhesins (TAA), which are important virulence factors of Gram-negative bacteria. BadA mediates the binding of B. henselae to extracellular matrix proteins and to endothelial cells, possibly via beta1-integrins, but prevents phagocytosis. Expression of BadA iscrucial for activation of hypoxia-inducible factor (HIF)-1 in host cells by B. henselae and secretion of proangiogenic cytokines (e.g., vascular endothelial growth factor,VEGF). BadA is immunodominant in B. henselae-infected patients and rodents, indicating that it is expressed during Bartonella infections. Our results suggest that BadA, the largest characterized bacterial protein thus far, is a major pathogenicity factor of B. henselae with a potential role in the induction of vasculoproliferative disorders. Currently, there are several projects ongoing aimed at the exact identification of BadA domain-function relationships.

The role of hypoxia-inducible factor (HIF)-1 in infections

HIF-1 has been identified as the key transcription factor involved in hypoxia adaptive processes and angiogenesis. However, there is increasing evidence that HIF-1 (in addition to its role in angiogenesis and cancer) may also be involved in inflammatory and infectious diseases. At present, these novel aspects of HIF-1 function are only poorly understood. Therefore, we suggest an essential role of HIF-1 in infections with human pathogens. Indeed, results revealed HIF-1 recent induced gene programming as excellent target for therapeutic intervention in infectious, inflammatory and neoplastic disease processes. Recently, we could demonstrate that HIF-1 plays an important role in the course of infection with Y. enterocolitica and other Enterobacteriaceae. Currently, we investigate the role of HIF-1 in infections with several pathogens in greater detail.

Ongoing

  • Domain-function analysis of BadA: Dr. Bettina Franz, Dr. Patrick Kaiser (postdoctoral fellows), Thomas Schmidgen (diploma student), Niklas Müller (medical student), Wibke Ballhorn (technician).
  • Analysis of HIF-1-activation in bacterial infections: Christiane Beerlage, (PhD student), Jessica Greb (medical student)
  • Interaction of human stem cells with B. henselae: Fiona O´Rourke (PhD student), Wibke Ballhorn (technician)
  • Gene regulation of pathogenicity factors in B. henselae: Elena Wüstenhagen (student), Julian Sommer (student), Dr. Bettina Franz (PostDoc)
  • Establishing new dynamic infection models: Ju Ik Chae (cand. med., Dr. Patrick Kaiser)

Team
Dr. rer. nat. Bettina Franz
Dr. rer. nat. Patrick Kaiser
Dipl.-Biol. Fiona O´Rourke
Dipl.-Biol. Christiane Beerlage
Dipl.-Biol. Thomas Schmidgen
Wibke Ballhorn
cand. rer. nat. Elena Wüstenhagen
cand. rer. nat. Julian Sommer
cand. med. Jessica Greb
cand. med. Ju Ik Chae

Collaborators

Prof. Kari AlitaloHelsinki, Finland
Prof. Burt AndersonTampa, Florida, USA
Prof. I. B. AutenriethTübingen, Germany
Prof. S. DimmelerFrankfurt am Main, Germany
Prof. Christoph DehioBasel, Switzerland
Prof. Holger K. EltzschigDenver, Colorado, USA
Dr. Dirk LinkeTübingen, Germany
Prof. Andrei LupasTübingen, Germany
Prof. Martin SchallerTübingen, Germany
Dr. Heinz SchwarzTübingen, Germany
Prof. Bernhard BrüneFrankfurt, Germany
Prof. Ralf BrandesFrankfurt, Germany
Prof. Adrian GoldmannHelsinki, Finland

 

Publications

  1. Kaiser, P.O., Linke, D., Schwarz, H., Kempf, V.A.J. Analysis of the modular contructed Bartonella adhesin A (BadA) reveals domain-specific and domain-overlapping functions in the process of host cell infection with Bartonella henselae. Cellular Microbiology 2011 (accepted).
  2. Müller, NF., Kaiser, P.O., Linke, D., Schwarz, H., Riess, T., Schäfer, A., Eble, J.A., Kempf, V.A.J. Trimeric autotransporter adhesin-dependent adherence of Bartonella henselae, Bartonella quintana and Yersinia enterocolitica to matrix components and endothelial cells under static and dynamic flow conditions. 2011 Jul;79(7):2544-53.).
  3. von Grumbkow, P., Zipp, A., Großkopf, B., Seidenberg, V., Fehren-Schmitz, L., Füldner, K., Kempf, V.A.J., Groß, U., Andersson, S.G., Herrmann, B., Hummel, S. Analysis to help identifying individuals from a historical mass grave in Kassel, Germany. American Journal of Physical Anthropology, 2011, doi: 10.1002/ajpa.21551.
  4. Schmidt, M.V., Paulus, P., Kuhn, A., Weigert, A., Morbitzer, V., Zacharowski, K., Kempf, V.A.J., Brüne, B., von Knethen, A.: PPARg-induced T-cell apoptosis reduces survival during polymicrobial sepsis. American Journal of Respiratory and Critical Care Medicine Jul 1;184(1):64-74.
  5. Sireis, W., Rüster, B., Dais, C., Hourfar, M.K., Capalbo, G., Pfeiffer, H.U., Janetzko, K., Goebel, M., Klüter, H., Schäfer, V., Kempf, V.A.J., Seifried, E., Schmidt, M. New strategies for rapid bacterial detection in platelets. 2011. Vox sanguinis ;101(3):191-9.
  6. Göttig S, Pfeifer Y, Wichelhaus TA, Zacharowski K, Bingold T, Averhoff B, Brandt C, Kempf VA. Global spread of New Delhi metallo-β-lactamase 1. Lancet Infect Dis. 2010 Dec;10(12):828-9.
  7. Buchmann, A.U., Kershaw,O, Kempf, VA.J. and Gruber, A.D. Does Feline leukemia virus pave the way for Bartonella henselae infection in cats? J Clin Microbiol 2010; 48(9):3295-300.
  8. Werth, N., Rosenberger, C., Yazdi, A.S., Edelmann, M., Amr, A., Beerlage, C., Bernhardt, W., von Eiff, C., Becker, K., Schäfer, A.,  Peschel, A., Kempf, V.A.J. Activation of hypoxia inducible factor 1 is a general phenomenon in infections with human pathogens. PLoS one 2010; 14;5(7):e11576.
  9. Doycheva, D., Pfannenberg C., Hetzel, J, Deuter, C.M., Pavesio, C., Kempf, V.A.J., Schuelen, E., Aschoff, P., Rao, N., Zierhut, M. Presumed Tuberculosis-induced Retinal Vasculitis, Diagnosed with Positron Emission Tomography (18F-FDG-PET/CT), Aspiration Biopsy, and Culture. Ocul Immunol Inflamm. 2010;18(3):194-9.
  10. Thaler, S., Grisanti, S., Klingel, K., Raible, A., Kempf, V.A.J., Schulte, B. Intermediate uveitis and arthralgia as early symptoms in Whipple’s disease. Int J Inf Dis 2010. Suppl 3:e388-9.
  11. Dietrich, F., Schmittgen, T., Maggi, R.G., Richter, D., Matuschka, F.R., Vonthein, R., Breitschwerdt, E., Kempf, V.A.J. Prevalence of Bartonella spp. and Borrelia spp. in Ixodes ricinus ticks and nymphs in Europe. Appl Env Microbiol 2010; 76(5):1395-8.
  12. Buchmann, A.U., Kempf, V.A.J., Kershaw, O., Gruber, A.D. Peliosis hepatis in cats is not associated with Bartonella henselae infection. Vet Pathol. 2010; 47(1):163-166.
  13. Maurer, G.D., Schittenhelm, J., Ernemann, U., Kempf, V.A.J., Ritz, R., Weller, M., Schmidt, F. POEMS syndrome with cutaneous and intracranial hemangioma. Journal of Neurology 2009; 257(3):484-7.
  14. Wicker, S., Rabenau, H.F., Brandt C., Kempf, V.A.J. Flu vaccination and healthcare workers: Self-protection and patient-protection (Influenzaimpfung bei medizinischem Personal: Selbstschutz und Patientenschutz). Deutsches Ärzteblatt 2010; 106(36):567-72.
  15. Gröbner, S., Kempf, V.A.J. Comparison of the BD GeneOhm StaphSR Assay with the Sa442/mecA-real-time-PCR for the detection of methicillin-resistant and –susceptible Staphylococcus aureus directly from positive blood culture bottles J Clin Microbiol 2009, 47(6):1689-1694.
  16. Eberhardt, C., S. Engelmann, H. Kusch, D. Albrecht, M. Hecker, I.B. Autenrieth and V. A. J. Kempf. Proteomic analysis of the bacterial pathogen Bartonella henselae and identification of immunogenic proteins for serodiagnosis. Proteomics 2009, 30;9(7):1967-1981.
  17. Haeberle, H., Dürrstein, C., Rosenberger, P., Kuhlicke, J., Kempf, V.A.J., Garofalo, R.P., Eltzschig, H.K.  Oxygen-independent stabilization of hypoxia inducible factor (HIF)-1 during respiratory syncytial virus infection PLoS one, 7;3(10):e3352.
  18. Kaiser, P.O., Riess, T., Wagner, C.L., Linke, D., Lupas, A., Schwarz, H., Raddatz, G., A. Schäfer, A.  and Kempf, V.A.J. The head of Bartonella adhesin A is crucial for host cell interaction of Bartonella henselae Cellular Microbiology, 10(11):2223-34.
  19. Szczesny, P., Martin, J., Ursinus, A., Baer, K., Linke, D., Riess, T., Kempf, V.A.J., Lupas, A., Zeth, K. Structure of the head of the Bartonella adhesin BadA (PLoS Pathogens, 2008 Aug 8;4(8):e1000119.
  20. Riess, T., Dietrich, F., Schmidt-K.V., Kaiser, P.O., Schwarz, H., Schäfer, A., Kempf, V.A.J. Analysis of a novel insect-cell culture-based growth medium for Bartonella spp. Appl Env Microbiol. 2008, 74(16):5224-7.
  21. Wagner, C.L., Riess, T., Linke, D., Eberhardt, C., Schäfer, A., Reutter, S., Kempf, V.A.J. Use of Bartonella adhesin A (BadA) immunoblotting in the serodiagnosis of Bartonella henselae infections. Int J Med Microbiol 2008 298(7-8):579-90.
  22. Gittinger, F.S., Raible, A., Kempf, V.A.J.: Nontuberculous infection of the parotid gland in an immunosuppressed adult. Journal of Medical Microbiology, 2008,
    57:536-9.
  23. Krüger, W.A., Kempf, V.A.J., Pfeiffer, M., Nagele, U., Unertl, K.E., Schroeder, T.H. Treatment of recurrent urosepsis caused by ESBL-producing Escherichia coli with tigecycline. J Clin Microbiol, 2008, 46(2):817-20.
  24. Hartmann, H., Eltzschig, H., Wurz, H., Hantke, K., Rakin, A., Yazdi, A.S., Matteoli, G., Bohn, E., Autenrieth, I.B., Karhausen, J., Neumann, D., Colgan, S.P., Kempf, V.A.J. Hypoxia-independent activation of HIF-1 by Enterobacteriaceae and their siderophores. Gastroenterology, 2008, 134(3):756-67.
  25. Gille, C., Leiber, A., Spring, B., Kempf V.A.J., Loeffler, J., Poets, C.F., Orlikowsky, T.W. Diminished phagocytosis-induced cell death (PI