Potential Roles for Regulatory Oxygenases in Rickettsial Pathogenesis
Abstract: Clinical and experimental evidence suggests an important role for oxidative stress and associated cellular defense mechanisms in the pathogenesis of vasculopathic rickettsioses. Our laboratory has reported that R. rickettsii infection of endothelial cells in vitro induces the expression of HO-1, the inducible isoform of the antioxidant defense enzyme heme oxygenase. HO-1 plays a critical role in maintaining the integrity of the vasculature and controls the functioning of the cyclooxygenase (COX) system. This study was undertaken to investigate the expression of COX and HO isozymes during in vitro infection of EC with two major representatives of spotted fever group Rickettsia species. The mRNA expression of COX-2 was significantly increased in endothelial cells infected with R. rickettsii and R. conorii, while that of COX-1 remained unaffected. Western blot analysis using total protein lysates from infected endothelial cells and corresponding uninfected controls further confirmed specific induction of COX-2 in response to infection. ELISA measurements on culture supernatants also suggested enhanced secretion of 6-keto PGF1? (stable hydrolysis product of PGI2 and PGE2. As a functional consequence of HO-1 upregulation, increased expression of the iron storage protein ferritin following R. rickettsii and R. conorii infection was also evident. Since products of HO-1 and COX-2 reactions govern a variety of physiologically important functions in the vasculature, further studies to define their regulation in the host cell should provide useful insights into the pathogenesis of rickettsial diseases.
endothelial cells heme oxygenase cyclooxygenase rickettsia species transcriptional regulators