A complex interaction between Rickettsia conorii and Dickkopf-1--potential role in immune evasion mechanisms in endothelial cells

PLoS One. 2012;7(9):e43638. doi: 10.1371/journal.pone.0043638. Epub 2012 Sep 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Boutonneuse Fever / genetics
  • Boutonneuse Fever / immunology*
  • Boutonneuse Fever / metabolism*
  • Case-Control Studies
  • Cell Line
  • Cytokines / immunology
  • Cytokines / metabolism
  • Endothelial Cells / immunology
  • Endothelial Cells / metabolism
  • Endothelial Cells / microbiology*
  • Female
  • Gene Silencing
  • Human Umbilical Vein Endothelial Cells / immunology
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / microbiology
  • Humans
  • Immune Evasion*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / immunology
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Interleukin-6 / metabolism
  • Male
  • Middle Aged
  • Rickettsia conorii / immunology
  • Rickettsia conorii / metabolism*
  • Signal Transduction
  • Thrombosis / genetics
  • Thrombosis / metabolism
  • Wnt Proteins / metabolism
  • Young Adult

Substances

  • Cytokines
  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-6
  • Wnt Proteins

Grant support

Sources of financial support are Norwegian Research Council, www.forskningsradet.no University of Oslo,uio.no, Helse Sør-Øst, www.helse-sorost.no. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.