MALDI Profiling and Imaging of Proteins and Drugs in a Rabbit Model of Tuberculosis

摘要

The use of imaging mass spectrometry was applied to the study of drug distribution and protein microenvironment in a rabbit model of tuberculosis. Rabbits infected with mycobacteria (M. bovis, bovine TB) exhibit much the same pathology as is observed in the human disease, including the development of pulmonary granulomas. Using a linear ion trap instrument, MALDI MS methods were optimized for the detection of the three main drugs used to treat TB: RIF [DHB: CAD of (M+Na+) at m/z 845], INH [CHCA: CAD of (M~(+)H~(+)) at m/z 138], and PZA [CHCA: CAD of (M+2H)~(+) at m/z 125]. Thus far, both RIF and PZA have been detected in the livers of dosed rabbits, and RIF has been detected in the liver of infected, dosed rabbits after sterilization. A small, inconsistent signal has also been observed for RIF in the lungs of infected, dosed rabbits. The effect of sterilizing radiation needs to be further studied, because while RIF can be detected in livers with and without radiation, the signal-to-noise ratio is worse after radiation, and may be a factor in the weak, inconsistent signal observed in the sterilized lung tissue. The protein microenvironment of the lung after infection was also analyzed via imaging mass spectrometry, with several proteins showing granuloma-specific localization (m/z 4,736 and 11,636). This tissue was also sterilized and the effects of the radiation on the proteome are unknown. This study is a first step in the analysis of the distribution of TB drugs in different lesions in an infected animal model of TB.