A world without tuberculosis: moving from imagination to reality

The treatment of individuals with LTBI with a 3-month, weekly treatment with isoniazid and rifapentine (3HP) has been previously shown to be efficacious in reducing the rate of TB progression (4). Sharan et al. used the macaque model of aerosol-based M. tuberculosis infection to show that 3HP is indeed efficacious in these model animals, as has been found in humans (3). Importantly, this manuscript goes beyond just confirming what is known from human clinical studies and provides crucial knowledge using the macaque model that distinguishes this study from human studies.

First, Sharan et al. conducted longitudinal PET/CT and CT analyses of the lungs of infected macaques at planned intervals after defined aerosol infection. By conducting in-depth CT analysis, the researchers showed that 3HP treatment reduced, and sometimes eliminated, granuloma formation. Secondly, Sharan et al. conclusively showed the presence of persistent M. tuberculosis bacilli in the lungs of macaques that were otherwise free of disease(3). For this purpose, they used simian immunodeficiency virus (SIV), related to human immunodeficiency viruses (HIVs) HIV-1 and HIV-2. In their lab, a model of M. tuberculosis and SIV coinfection had been developed and shown to lead to a massive depletion of lung CD4+ T cells and reactivation of LTBI (5, 6). The authors utilized SIV coinfection strategically — to observe if there were differences in the extent of persistent M. tuberculosis that remained as a function of 3HP treatment (3). This experiment was warranted because it is challenging to radiologically distinguish between macaques with LTBI and those that have cleared the infection. With their SIV coinfection model, the authors used PET/CT and CT scans to conclusively show that most 3HP-treated macaques had sterilized the infection, while all of the untreated animals had evidence of LTBI reactivation.

Finally, it was possible for Sharan and colleagues to subject the lungs of treated and untreated macaques to CFU analysis at the endpoint to validate the imaging results, whereas it is impossible to carry out such a study in humans (3). Sharan et al. conclusively showed that 3HP treatment reduced the levels of M. tuberculosis bacilli in the lungs of this cohort of macaques, such that SIV coinfection was unable to result in increased bacillary replication. In contrast, increased M. tuberculosis levels were observed in the control group. The combined results underscore the power of aerosol TB infection in the macaque model; it is possible to longitudinally evaluate TB disease in the lungs as a function of infection, coinfection, and treatment, but also possible to identify the total lung disease burden at necropsy. While this experiment is important because it validates earlier findings that 3HP treatment is efficacious for LTBI, it also opens the door for testing more chemotherapies and immunotherapies using the LTBI model and the SIV coinfection approach (3).

This study (3) marks an important step toward eradicating TB, as the drug combination kills both the actively growing M. tuberculosis and the M. tuberculosis persisters. The M. tuberculosis macaque model is excellent for the study of LTBI, and advances in PET and CT scanning have provided critical tools with which to follow M. tuberculosis infections. I firmly believe that it is an inspiring time for TB research. In the last 35 years, we have developed a complete set of tools to manipulate M. tuberculosis (7). Whole genome sequencing of M. tuberculosis provided the full complement of genes (8, 9) and paved the way for microarrays to study gene expression of actively growing, dying, or persistent M. tuberculosis cells (10). Genetics, biochemistry, and X-ray crystallography have allowed for the elucidation of isoniazid action (11). M. tuberculosis isoniazid persisters can be reproducibly generated in vitro (12) but are eliminated with isoniazid in combination with agents that stimulate respiration (13). Interestingly, isoniazid and rifapentine successfully combined to sterilize M. tuberculosis cells, including persisters (3). Although a human clinical trial is justified, it is more complicated to demonstrate the sterilization of M. tuberculosis in humans. If this sterilization can be reproduced in mice, it would provide a cost-effective way to test whether the sterilization is specific to the CDC1551 strain of M. tuberculosis used in this study (3) or is more broadly applicable. In addition, chemotherapies to further shorten the treatment could be identified. Further testing in genetically modified mouse models could determine whether adaptive or innate immunity plays a role in the sterilization observed with these drug combinations.

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