The obligate intracellular bacteria belonging to Rickettsiaspecies are etiological agents of the spotted fever and typhus groups (SFG and TG) of rickettsial diseases in almost all geographic locations worldwide. Rocky Mountain spotted fever and epidemic typhus, caused respectively by R. rickettsii and R. prowazekii, are serious infections that can be fatal in children, elderly, and immunodeficient or misdiagnosed/untreated patients. A major clinical hallmark is the infection of endothelial cell lining of vessels, ultimately leading to vascular damage and associated pathologies. The ongoing research projects in my laboratory are focused on the following aspects of rickettsial pathogenesis:
1. Rickettsia rickettsii infects and proliferates predominantly within vascular endothelial cells, which respond by activating a series of distinct signal transduction pathways. R. rickettsii infection of endothelial cells results in the activation of nuclear factor-kappaB (NF-kB), a transcription factor which controls the expression of an array of genes involved in bacterial infections, immune response, and apoptosis. The anti-apoptotic functions of NF-kB are critical for the protection of host cell from apoptotic death during R. rickettsii infection. One of our major goals is to further our understanding of signaling mechanisms underlying Rickettsia-induced transcriptional activation, to evaluate their participation in the host cell response to infection, and to investigate if interfering with these signals affects rickettsial replication.
2. Vascular endothelium is a multifunctional endocrine and paracrine organ involved in the modulation of blood flow and vessel tone, coagulation, and regulation of immune and inflammatory responses. In various diseases, harmful effects of reactive oxygen species (ROS) play an important role in endothelial dysfunction. Our goal is to elucidate regulatory mechanisms controlling redox homeostasis, acute inflammation, and vascular permeability in the host vasculature during Rickettsia infection to identify new and unique targets for therapeutic interventions.
3. While apoptosis serves as an important host defense mechanism to restrict proliferation and ensuing pathogenesis during bacterial infections, intracellular rickettsiae require intimate association with the target host cells for their growth/spread. It is thus possible that like other intracellular pathogens, rickettsiae may also utilize strategies to inhibit host apoptosis early during the infection for sake of their own survival. Identified and described by our laboratory, one such strategy during endothelial cell infection of R. rickettsii is the activation of NF-kB, but nothing is known about cell signaling events during infection with and potential antiapoptotic activities of typhus group organisms. To address this critical gap in the existing knowledge of rickettsial pathogenetic mechanisms is highly significant because of distinctive differences in the intracellular behavior of SFG and TG organisms and the potential for intentional use of R. prowazekii (Class B on CDC list) and R. rickettsii (Category C) as bioterror agents.