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One Size Fits All? Not in In Vivo Modeling of Tuberculosis Chemotherapeutics

2021.03.16.

Hee-Jeong Yang, Decheng Wang, Xin Wen, Danielle M. Weiner, Laura E. Via; Frontiers in Cellular and Infection Microbiology, 2021

Summary

Tuberculosis (TB) remains a global health problem despite almost universal efforts to provide patients with highly effective chemotherapy, in part, because many infected individuals are not diagnosed and treated, others do not complete treatment, and a small proportion harbor Mycobacterium tuberculosis (Mtb) strains that have become resistant to drugs in the standard regimen. Development and approval of new drugs for TB have accelerated in the last 10 years, but more drugs are needed due to both Mtb’s development of resistance and the desire to shorten therapy to 4 months or less. The drug development process needs predictive animal models that recapitulate the complex pathology and bacterial burden distribution of human disease. The human host response to pulmonary infection with Mtb is granulomatous inflammation usually resulting in contained lesions and limited bacterial replication. In those who develop progressive or active disease, regions of necrosis and cavitation can develop leading to lasting lung damage and possible death. This review describes the major vertebrate animal models used in evaluating compound activity against Mtb and the disease presentation that develops. Each of the models, including the zebrafish, various mice, guinea pigs, rabbits, and non-human primates provides data on number of Mtb bacteria and pathology resolution. The models where individual lesions can be dissected from the tissue or sampled can also provide data on lesion-specific bacterial loads and lesion-specific drug concentrations. With the inclusion of medical imaging, a compound’s effect on resolution of pathology within individual lesions and animals can also be determined over time. Incorporation of measurement of drug exposure and drug distribution within animals and their tissues is important for choosing the best compounds to push toward the clinic and to the development of better regimens. We review the practical aspects of each model and the advantages and limitations of each in order to promote choosing a rational combination of them for a compound’s development. 

Results from MultiScan™ LFER PET/CT

Tuberculosis Imaging group under the direction of Laura E. Via is using 2 MultiScan™ LFER PET/CT scanner for studying tuberculosis on Rabbit, Common Marmoset and Rhesus Macaque at National Institute of Allergy and Infectious Diseases.

In this substantial comprehensive review, the researchers also compared these 3 animal models in respect of PET/CT imaging:

  • In longitudinal studies that combined PET/CT imaging, using FDG injected IV as a probe for metabolic activity, FDG concentrated in metabolically active regions within the MtbHN878 lesions as they developed, but as necrosis progressed, the acellular centers of granulomas and cavities accumulated less FDG due to the lack of live cells (Figure 3A)
  • NHP models are amenable to most diagnostic and therapeutic methods used in clinical studies, such as medical imaging (Figures 3B, C), serial blood sampling, and bronchoalveolar lavage (BAL) sampling for pharmacokinetic monitoring within an individual (Lewinsohn et al., 2006; Lin et al., 2013; Via et al., 2013). As serial imaging is feasible, methods to follow both individual lesion development and regression PI have been developed

Figure 3. FDG PET/CTs of a rabbit (A), marmoset (B), and rhesus macaque (C) with cavitary disease. The animals were infected for 69 to 90 days with M. tuberculosis at the time of imaging. Cavities (blue arrows) have been partially emptied of their necrotic contents and filled with air indicated by a darker central region in the lesions (lower density) surrounded by lighter walls (higher density). The scales show the range of CT Hounsfield units from higher to low density in shades of gray (+400 to −1000) on the left and FDG uptake in PET standard uptake units / body weight from high to low uptake in bright yellow to red to black (14 to 0) on the right. The width of the animal’s midsection is indicated with a bar and label to highlight the difference in size of the three animals.

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