Non-invasive Optical Imaging of Select Agent Bacteria in Non-human Primates

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There is an urgent need to develop more effective vaccines and antibiotic regimens against many of the Select Agent bacteria that cause lethal infection in humans. This is particularly true for the candidate bioterrorism agents, Burkholderia. pseudomallei (Bp) and Burkholderia mallei (Bm), the causative agents of human melioidosis and glanders. These Gram negative, facultative intracellular pathogens share many common features of their genetics, pathogenesis, host immune response and clinical pathology. B. mallei primarily infect solipeds but the disease is transmissible to humans by ingestion and cutaneous or aerosol exposures. Concern over this bacterium and the very closely related species B. pseudomallei has heightened because of the pathogens' seemingly perfect characteristics for malevolent uses as bioterror or biowarfare weapons against both animals and humans. In modern times their potential destructive impact on public health has escalated due to the pathogens' opportunistic infection of diabetic and immunocompromised people, two growing populations worldwide. For both pathogens, severe infection in humans carries a high mortality rate, all are recalcitrant to antibiotic therapy and no licensed vaccine exists for either prophylactic or therapeutic use. Small animal models of infectious disease play a central role in research programs aimed at identifying leads and approaches that could be exploited to devise improved diagnostics, pre-treatments and therapies against bioterrorism agents. However, the further development of promising leads is dependent on additional animal models of infection which more faithfully represent humans. It is clear that the large body of high quality biodefense research currently funded by NIAID will identify promising new approaches to disease control, and that the development of these approaches will be dependent on reliable, reproducible and relevant models of infection. With this in mind we propose a UO1 project to develop non-human primate models of melioidosis and glanders which allow the direct optical imaging of the infection. This work builds on our current NIAID projects to devise non-human primate models of tularaemia and melioidosis. The ability to image the infection will provide a significant advantage over more conventional non-human primate models of disease, because it allows additional data on the temporal and spatial pattern of the infection to be gathered from each animal. In addition, we believe it will be possible to gather data on the metabolic status of the bacteria in tissues. The additional data acquired by optical imaging of the infection will have benefits in providing additional information to support preclinical studies and advancement of products into phase I clinical safety trials in humans. Also, the ability to acquire additional data from each animal could reduce the overall numbers of animal used in these programmes, for example by providing multiple time point data from a single animal. We believe that the development of sensitive, non-invasive imaging techniques which can be applied to non human primates is an essential step in the generation of future clinical interventions to Select Agent bacteria. The purpose of this application is to apply recent advances in whole animal bioluminescent and fluorescent imaging to study the pathogenesis and treatment of melioidosis and glanders in marmosets. This will be complemented by genome-wide transcriptional microarray analysis of whole blood from infected animals to provide an in-depth view of the immunological response to infection. Given the high cost and logistical constraints of non-human primate studies conducted in containment, combining these non- lethal analytical approaches will provide a comprehensive picture of the dynamics of infection and response to treatment, while reducing the number of animals needed for each study. PHS 398/2650 (Rev. 11/07) Page 12 Continuation Format Page