Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY Tick-borne rickettsial diseases (TBRDs) are ubiquitously present throughout the world and case fatality rates in disease clusters can range up to 100% despite the availability of effective treatment. Thus, there is a need to increase the “tool box” for TBRD control by supplementing existing strategies with promising novel approaches that focus on interrupting the Rickettsia transmission cycle in the tick vector. Our recent studies demonstrated that the non-pathogenic Candidatus Rickettsia andeanae is secreted in tick saliva during feeding, but at a lower level when compared to pathogenic Rickettsia parkeri, raising questions regarding the underlying mechanisms that mediate rickettsial pathogenicity. The likelihood that rickettsiae manipulate the arthropod host to enhance horizontal transmission has been recognized, yet the specific interactions between Rickettsia and ticks remains unknown. Unfortunately, significant knowledge gaps exist regarding the basic transmission biology of tick-borne Rickettsia and the specific interactions between Rickettsia and tick physiology that enable transmission, which represents a significant barrier to the field and has limited the development of novel approaches to control TBRDs. Thus, the premise of this proposal is that pathogenic Rickettsia, but not non-pathogenic strains of Rickettsia, alter regulation of tick-derived proteins to enhance salivary gland physiology and increase the secretory activity of the gland, which facilitates increased horizontal transmission. Salivary gland function is dependent on strict regulation of acini membrane physiology and thus, we hypothesize that Rickettsia alter mechanisms for ionic homeostasis to facilitate horizontal transmission. Correspondingly, we hypothesize that inhibition of ion flux will negate the rickettsial-mediated enhancement of salivary gland activity to prevent tick bloodmeal feeding and horizontal transmission of Rickettsia. In Specific Aim 1, we will employ a multidisciplinary approach to measure the influence pathogenic Rickettsia has to secretory activity and membrane physiology (e.g. membrane potential) of an R. parkeri infected tick salivary gland compared to non- pathogenic Rickettsia infected ticks. These data will delineate the mechanism by which Rickettsia influences tick salivary gland physiology to drive pathogenicity. In Specific Aim 2, we will test if dysregulation of K+ homeostasis across salivary gland epithelia will inhibit salivary gland function of rickettsemic ticks to alter blood feeding biology and reduce R. parkeri virulence in vertebrate disease models. Combined, the experiments outlined in his proposal will define unique aspects of rickettsial influence on tick physiology that enhance pathogenicity of Rickettsia, which will assist in resolving the epidemiology of SFG Rickettsia and reveal intervention points to reduce the health burden of TBRDs.
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