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Increased Levels of Soluble CD40L in African Tick Bite Fever: Possible Involvement of TLRs in the Pathogenic Interaction between Rickettsia africae, Endothelial Cells, and Platelets¹

Jan K. Damås^2,*,, Mogens Jensenius, Thor Ueland^*, Kari Otterdal^*, Arne Yndestad^*, Stig S. Frøland^*,, Jean-Marc Rolain, Bjørn Myrvang, Didier Raoult and Pål Aukrust^*,

^* Research Institute for Internal Medicine, Rikshospitalet University Hospital, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Rikshospitalet University Hospital, Oslo, Norway; Department of Infectious Diseases, Ullevål University Hospital, University of Oslo, Oslo, Norway; and Unite des Rickettsies, Faculte de Medecine, Universite de la Mediterranee, Marseille, France

The pathophysiological hallmark of spotted fever group rickettsioses comprises infection of endothelial cells with subsequent infiltration of inflammatory cells. Based on its ability to promote inflammation and endothelial cell activation, we investigated the role of CD40L in African tick bite fever (ATBF), caused by Rickettsia africae, using different experimental approaches. Several significant findings were revealed. 1) Patients with ATBF (n = 15) had increased serum levels of soluble CD40 ligand (sCD40L), which decreased during follow-up. 2) These enhanced sCD40L levels seem to reflect both direct and indirect (through endothelial cell activation involving CX3CL1-related mechanisms) effects of R. africae on platelets. 3) In combination with sCD40L, R. africae promoted a procoagulant state in endothelial cells by up-regulating tissue factor and down-regulating thrombomodulin expression. 4) Although the R. africae-mediated activation of platelets involved TLR2, the combined procoagulant effects of R. africae and sCD40L on endothelial cells involved TLR4. 5) Doxycycline counteracted the combined procoagulant effects of R. africae and sCD40L on endothelial cells. Our findings suggest an inflammatory interaction between platelets and endothelial cells in ATBF, involving TLR-related mechanisms. This interaction, which includes additive effects between sCD40L and R. africae, may contribute to endothelial inflammation and hypercoagulation in this disorder.

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