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Published on: August 14, 2017
von Willebrand factor release and thrombomodulin and tissue factor expression in Rickettsia conorii-infected
N Teysseire1, D Arnoux, F George
1Unité des Rickettsies, Faculté de Médecine, Hôpital de la Conception, Marseille, France.
Abstract:
Mediterranean spotted fever, a tick-borne rickettsiosis caused by Rickettsia conorii, may lead to small-vessel or deep-vein thrombosis. In order to evaluate the role of endothelial cell alteration in this lesion, we infected human endothelial cells derived from umbilical veins with R. conorii. We report the induction of two previously unreported prothrombotic mechanisms in rickettsial disease: (i) a progressive decline in thrombomodulin antigen and (ii) early expression of tissue factor, and, as described for R. rickettsii infection, later release of von Willebrand factor from Weibel-Palade bodies. Thrombomodulin expression in infected endothelial cells, measured by the thrombin-dependent activation of protein C or flow cytometric analysis, decreased steadily between 4 and 24 h after inoculation with rickettsiae. R. conorii infection induced tissue factor expression, measured by clotting assay and flow cytometric analysis, which was detectable 2 h postinoculation, reached its maximum 4 h postinoculation, and progressively decreased thereafter. Infection resulted in a relatively late release of von Willebrand factor antigen into the culture medium. A double-label immunofluorescence assay for the simultaneous evaluation of von Willebrand factor and R. conorii showed that the depletion of cytoplasmic von Willebrand factor stored in Weibel-Palade bodies was due to a direct effect of the intracellular R. conorii. These disturbances of endothelial function observed with R. conorii-infected cells may provide a paradigm for the elucidation of thrombotic pathobiology with Mediterranean spotted fever.
Insights
Mediterranean spotted fever, caused by Rickettsia conorii, can lead to thrombosis. This study reveals R. conorii infection alters endothelial cells, promoting clot formation through thrombomodulin decline and tissue factor expression.
Area of Science:
- Vascular Biology
- Infectious Diseases
- Hematology
Background:
- Mediterranean spotted fever is a tick-borne illness caused by Rickettsia conorii.
- Rickettsial infections can lead to thrombotic events, including deep-vein thrombosis.
- The precise mechanisms by which Rickettsia conorii induces endothelial dysfunction and thrombosis are not fully understood.
Purpose of the Study:
- To investigate the role of endothelial cell alterations in the pathogenesis of thrombosis associated with Rickettsia conorii infection.
- To identify specific prothrombotic mechanisms induced by R. conorii in human endothelial cells.
Main Methods:
- Infection of human umbilical vein endothelial cells (HUVECs) with Rickettsia conorii.
- Measurement of thrombomodulin expression using thrombin-dependent protein C activation and flow cytometry.
- Assessment of tissue factor expression via clotting assays and flow cytometry.
- Quantification of von Willebrand factor release into the culture medium.
- Double-label immunofluorescence to visualize R. conorii and von Willebrand factor colocalization.
Main Results:
- R. conorii infection caused a progressive decline in thrombomodulin antigen expression on endothelial cells between 4 and 24 hours post-infection.
- Early expression of tissue factor was induced by R. conorii, detectable at 2 hours and peaking at 4 hours post-infection.
- A late release of von Willebrand factor antigen from Weibel-Palade bodies was observed.
- Immunofluorescence confirmed that intracellular R. conorii directly caused the depletion of von Willebrand factor from Weibel-Palade bodies.
Conclusions:
- Rickettsia conorii infection induces prothrombotic changes in endothelial cells, including decreased thrombomodulin and increased tissue factor expression.
- These endothelial disturbances contribute to the thrombotic pathobiology of Mediterranean spotted fever.
- The findings provide a cellular model for understanding thrombosis in rickettsial diseases.
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