Applications of In Vivo Imaging in the Evaluation of the Pathophysiology of Viral and Bacterial Infections and in Development of Countermeasures to BSL3/4 Pathogens

摘要

While preclinical and clinical imaging have been applied to drug discovery/development and characterization of disease pathology, few examples exist where imaging has been used to evaluate infectious agents or countermeasures to biosafety level (BSL)3/4 threat agents. Viruses engineered with reporter constructs, i.e., enzymes and receptors, which are amenable to detection by positron emission tomography (PET), single photon emission tomography (SPECT), or magnetic resonance imaging (MRI) have been used to evaluate the biodistribution of viruses containing specific therapeutic or gene transfer payloads. Bioluminescence and nuclear approaches involving engineered reporters, direct labeling of bacteria with radiotracers, or tracking bacteria through their constitutively expressed thymidine kinase have been utilized to characterize viral and bacterial pathogens post-infection. Most PET, SPECT, CT, or MRI approaches have focused on evaluating host responses to the pathogens such as inflammation, brain neurochemistry, and structural changes and on assessing the biodistribution of radiolabeled drugs. Imaging has the potential when applied preclinically to the development of countermeasures against BSL3/4 threat agents to address the following: (1) presence, biodistribution, and time course of infection in the presence or absence of drug; (2) binding of the therapeutic to the target; and (3) expression of a pharmacologic effect either related to drug mechanism, efficacy, or safety. Preclinical imaging could potentially provide real-time dynamic tools to characterize the pathogen and animal model and for developing countermeasures under the U.S. FDA Animal Rule provision with high confidence of success and clinical benefit.