Affiliation: Department of Microbiology and Immunology, P.O. Box 672, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Spotted fever rickettsioses due to Rickettsia rickettsii and R. conorii and epidemic typhus caused by R. prowazekii have been known to humankind since the beginning of the 20th century. Alarmingly, new species/subspecies of arthropod-borne rickettsiae are still being recognized and described as globally emerging pathogens. The genus Rickettsia includes obligate intracellular α-proteobacteria with affinity to infect vascular endothelium of small and medium-sized blood vessels in humans. Endothelial cells, key immunoreactive cells involved in host defense and inflammation, are intimately involved in the manifestations of rickettsial infections. The present review features the current understanding of cell signaling, host response, and apoptotic death mechanisms during in vitro infection of cultured human umbilical vein endothelial cells or endothelial-like cell lines with pathogenic rickettsiae and summarizes critical roles for infectioninduced oxidative stress, nuclear factor-kappa B, and p38 MAP kinase pathways in the regulation of innate immune responses and in preventing apoptosis early during infection to ensure host cell survival for rickettsial replication/spread. However, in the context of emerging concept of ‘endothelial heterogeneity’, the existing knowledge pertaining to the interactions of these unique intracellular pathogens with endothelial cells of different vascular beds remains in its infancy. A complete definition of signaling interactions between organ-specific host endothelial cells and strains of varying virulence and further detailed characterization of direct in vivo models of disseminated vascular infection represent major steps in advancing our depth of understanding of rickettsial pathogenesis, which should allow the development of novel antiinflammatory strategies to combat the pathologic sequelae of debilitating human rickettsioses.