Pathogenic Mechanisms of Diseases Caused byRickettsia

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Abstract
The specter of bioterrorism employing genetically engineered Rickettsia resistant to all antibiotics should reawaken the world's desire to elucidate the pathogenesis of typhus and spotted fever rickettsioses in a search for mechanisms vulnerable to interdiction. The pathogenetic sequence includes rickettsial entry into the dermis, hematogenous dissemination to vascular endothelial cells (most critically in brain and lungs), increased vascular permeability, edema, and immunity mediated by NK cells, IFN‐γ, TNF‐α, RANTES, antibodies, and cytotoxic T lymphocytes. Silverman has demonstrated the role of reactive oxygen species (ROS) produced by R. rickettsii‐infected endothelial cells in peroxidative damage to cell membranes in vitro, and Heinzen has described actin‐based rickettsial intracellular mobility and intercellular spread. At this point the availability of sequences of rickettsial genomes and excellent animal models of rickettsioses have yielded insufficient progress towards the identification of rickettsial virulence factors and knowledge of the importance of injury mediated by ROS, phospholipase A2, protease(s) or other mechanisms in vivo. Attention to the rickettsiosis‐associated procoagulant state led to determination that hemostatic mechanisms largely prevent major hemorrhage without disseminated intravascular coagulation or thrombosis‐mediated ischemia. Particularly lacking is knowledge of early events in vivo at the portal of entry in skin (or lung), of the effects of the inoculum medium (arthropod saliva or feces), mediators produced by infected endothelium under conditions of flow and of the contributions in vivo of immune effectors to pathology, of the role of apoptosis in rickettsial infection, and of the endothelial cell alterations that account for increased vascular permeability. The host cell receptor for the Rickettsia ligand and the mechanism of rickettsial escape from the phagosome need to be elucidated.