Tools for monitoring response to tuberculosis (TB) treatment are time-consuming and resource intensive. Noninvasive biomarkers have the potential to accelerate TB drug development, but to date, little progress has been made in utilizing imaging technologies. Therefore, in this study, we used noninvasive imaging to monitor response to TB treatment. BALB/c and C3HeB/FeJ mice were aerosol infected with Mycobacterium tuberculosis and administered bactericidal (standard and highly active) or bacteriostatic TB drug regimens. Serial pulmonary [18 F]-2-fluoro-deoxy-D-glucose (FDG) positron emission tomography (PET) was compared with standard microbiologic methods to monitor the response to treatment. [18 F]FDG-PET correctly identified the bactericidal activity of the drug regimens. Imaging required fewer animals; was available in real time, as opposed to having CFU counts 4 weeks later; and could also detect TB relapse in a time frame similar to that of the standard method. Lesion-specific [18 F]FDG-PET activity also broadly correlated with TB treatment in C3HeB/FeJ mice that develop caseating lesions. These studies demonstrate the application of noninvasive imaging to monitor TB treatment response. By reducing animal numbers, these biomarkers will allow costeffective studies of more expensive animal models of TB. Validated markers may also be useful as "point-ofcare" methods to monitor TB treatment in humans.New and shorter drug regimens for tuberculosis (TB) are needed to support global control efforts. However, tools for monitoring TB drug treatment in preclinical studies and clinical trials are time-consuming and resource intensive. For instance, typical phase 3/4 trials entail treating hundreds of patients for at least 6 months and monitoring them for at least 1 year for relapse. Phase 2 studies that monitor patients for 8 weeks for sputum culture conversion are limited because sputum bacterial burdens are not available in real time and do not always correlate closely with overall pulmonary disease. This situation is unlike clinical trials evaluating treatments against human immunodeficiency virus infection, where quantitative viral loads and CD4 counts provide well-validated biomarkers of disease burden and progression of disease, respectively. With the alarming rise of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis infections, which account for up to 20% and 2%, respectively, of the global TB disease burden (6), there is significant interest in the use of validated biomarkers to monitor TB treatment in patients. Since clinical indicators can often be misleading, these biomarkers may allow more rapid identification of patients who relapse or respond poorly to TB treatment. The TB Trials Consortium (TBTC) has expressed an urgent need for development of validated biomarkers for monitoring and detecting relapse during and after TB treatment in patients (29). Several biomarker technologies for monitoring TB treatment are under development, though none utilize imaging technologies (24). A...

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COVID-19 continues to exact a toll on human health despite the availability of several vaccines. Bacillus Calmette Guerin (BCG) has been shown to confer heterologous immune protection against viral infections including COVID-19 and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model together with immune profiling and single cell RNA sequencing (scRNAseq). We observed that BCG reduced both lung SCV2 viral load and bronchopneumonia. This was accompanied by an increase in lung alveolar macrophages, a reversal of SCV2-mediated T cell lymphopenia, and reduced lung granulocytes. Single cell transcriptome profiling showed that BCG uniquely recruits immunoglobulin-producing plasma cells to the lung suggesting accelerated antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, and differentially expressed gene (DEG) analysis showed a transcriptional shift away from exhaustion markers and towards antigen presentation and repair. Similarly, BCG enhanced lung recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, with both cell-types also showing reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations.

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