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-gamma,
TNF-alpha,
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 A(2),
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.