A Complex Interaction between Rickettsia conorii and Dickkopf-1 - Potential Role in Immune Evasion Mechanisms in Endothelial Cells

Elisabeth Astrup, Tove Lekva, Giovanni Davì, Kari Otterdal, Francesca Santilli, Erik Øie, Bente Halvorsen, Jan Kristian Damås, Didier Raoult, Giustina Vitale, Juan P. Olano, Thor Ueland, Pål Aukrust

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The pathophysiological hallmark of spotted fever group rickettsioses comprises vascular inflammation. Based on the emerging importance of the wingless (Wnt) pathways in inflammation and vascular biology, we hypothesized that Dickkopf-1 (DKK-1), as a major modulator of Wnt signaling, could be involved in the pathogenesis in rickettsial infections. Our major findings were: (i) While baseline concentration of DKK-1 in patients with R. conorii infection (n = 32) were not different from levels in controls (n = 24), DKK-1 rose significantly from presentation to first follow-up sample (median 7 days after baseline). (ii) In vitro experiments in human umbilical vein endothelial cells (HUVECs) showed that while heat-inactivated R. conorii enhanced the release of interleukin-6 (IL-6) and IL-8, it down-regulated the release of endothelial-derived DKK-1 in a time- and dose-dependent manner. (iii) Silencing of DKK-1 attenuated the release of IL-6, IL-8 and growth-related oncogene (GRO)α in R. conorii-exposed HUVECs, suggesting inflammatory effects of DKK-1. (iv) Silencing of DKK-1 attenuated the expression of tissue factor and enhanced the expression of thrombomodulin in R. conorii-exposed HUVECs suggesting pro-thrombotic effects of DKK-1. The capacity of R. conorii to down-regulate endothelial-derived DKK-1 and the ability of silencing DKK-1 to attenuate R. conorii-induced inflammation in endothelial cells could potentially reflect a novel mechanism by which R. conorii escapes the immune response at the site of infection.

Original languageEnglish (US)
Article numbere43638
JournalPloS one
Volume7
Issue number9
DOIs
StatePublished - Sep 18 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Astrup, E., Lekva, T., Davì, G., Otterdal, K., Santilli, F., Øie, E., Halvorsen, B., Damås, J. K., Raoult, D., Vitale, G., Olano, J. P., Ueland, T., & Aukrust, P. (2012). A Complex Interaction between Rickettsia conorii and Dickkopf-1 - Potential Role in Immune Evasion Mechanisms in Endothelial Cells. PloS one, 7(9), [e43638]. https://doi.org/10.1371/journal.pone.0043638