No abstract

There is urgent need for new drug regimens that more rapidly cure tuberculosis (TB). Existing TB drugs and regimens vary in treatment-shortening activity, but the molecular basis of these differences is unclear, and no existing assay directly quantifies the ability of a drug or regimen to shorten treatment. Here, we show that drugs historically classified as sterilizing and non-sterilizing have distinct impacts on a fundamental aspect of Mycobacterium tuberculosis physiology: ribosomal RNA (rRNA) synthesis. In culture, in mice, and in human studies, measurement of precursor rRNA reveals that sterilizing drugs and highly effective drug regimens profoundly suppress M. tuberculosis rRNA synthesis, whereas non-sterilizing drugs and weaker regimens do not. The rRNA synthesis ratio provides a readout of drug effect that is orthogonal to traditional measures of bacterial burden. We propose that this metric of drug activity may accelerate the development of shorter TB regimens.

Introduction Severe Acute Respiratory Syndrome coronavirus 2 (SARS-COV-2 or COVID-19) has detrimental impacts on healthcare systems over the globe and ripple effects on every aspect of human life [1, 2]. The COVID-19 pandemic has caused governments to put their countries on an unprecedented pause in at least three months to flatten the contagion curve [3]. Shutdown border, travel restriction, social distancing, and social isolation have been imposed to limit the spread of viruses, which may spark the fear of an impending economic crisis and recession [4-6].

Background Although QuantiFERON-TB Gold Plus (QFT-Plus), a new interferon-gamma release assay, has shown good performance in adults, little data is available in children. Methods De-identified data from TB-suspected patients age <18 years with QFT-Plus results, who were admitted or screened at the National Lung Hospital (NLH) in Ha Noi, Vietnam in 2017, were assessed. Logistic regression analyses were performed to determine the characteristics associated with having a positive QFT-Plus result. Sensitivity, both overall and in subgroups of pulmonary TB only (PTB), extra-pulmonary TB (EPTB) only, and both PTB and EPTB were calculated. Results Of 222 children with available QFT-Plus results, 33 were classified as confirmed TB, of whom 18 had QFT-Plus (+) and 15 had QFT-Plus (-). Multiple logistic regression modeling suggested that age, history of TB, and confirmed TB were significantly associated with having a positive QFT-Plus result with an area under the ROC curve of 0.77. QFT-Plus sensitivity in PTB only, EPTB, and both PTB and EPTB patients was 84.2%, 14.3% and 14.3%, respectively. The overall sensitivity of the QFT-Plus assay (regardless PTB or EPTB) in children was 54.5%. Conclusion Although QFT-Plus had a good sensitivity in children having exclusive PTB, it had poor sensitivity in EPTB.

Mycobacterium tuberculosis (Mtb) is responsible for approximately 1.5 million deaths each year. Though 10% of patients develop tuberculosis (TB) after infection, 90% of these infections are latent. Further, mice are nearly uniformly susceptible to Mtb but their M1-polarized macrophages (M1-MΦs) can inhibit Mtb in vitro, suggesting that M1-MΦs may be able to regulate anti-TB immunity. We sought to determine whether human MΦ heterogeneity contributes to TB immunity. Here we show that IFN-γ-programmed M1-MΦs degrade Mtb through increased expression of innate immunity regulatory genes (Inregs). In contrast, IL-4-programmed M2-polarized MΦs (M2-MΦs) are permissive for Mtb proliferation and exhibit reduced Inregs expression. M1-MΦs and M2-MΦs express pro- and anti-inflammatory cytokine-chemokines, respectively, and M1-MΦs show nitric oxide and autophagy-dependent degradation of Mtb, leading to increased antigen presentation to T cells through an ATG-RAB7-cathepsin pathway. Despite Mtb infection, M1-MΦs show increased histone acetylation at the ATG5 promoter and pro-autophagy phenotypes, while increased histone deacetylases lead to decreased autophagy in M2-MΦs. Finally, Mtb-infected neonatal macaques express human Inregs in their lymph nodes and macrophages, suggesting that M1 and M2 phenotypes can mediate immunity to TB in both humans and macaques. We conclude that human MФ subsets show unique patterns of gene expression that enable differential control of TB after infection. These genes could serve as targets for diagnosis and immunotherapy of TB.