Advances in basic and translational tuberculosis research: Proceedings of the first meeting of RePORT international

Abstract

RePORT International is a collaborative research network of investigators from multiple countries and institutions with the goal of establishing a bio-repository of specimens and clinical data for the study of active TB and latent TB infection (LTBI). During the first meeting of RePORT International in Boston, Massachusetts, the results of research pertinent to TB control and eradication were presented, including advances in the research of Mycobacterium tuberculosis (MTB) persistence and drug resistance, TB diagnostics, drug and vaccine development.

Keywords: Advances; RePORT; Research; Tuberculosis.

Figure 1 -

Vitamin C sterilizes drug-susceptible and drug-resistant M. tuberculosis strains (a) M. tuberculosis H37Rv cultures grown to an OD600nm of ≈ 0.75 were diluted 1/20 and treated with increasing amounts of vitamin C (VC, from 0.1 mM to 4 mM). 1 mM* represents an experiment where 1 mM of vitamin C was added to the culture daily for the first 4 days of treatment. (b) M. tuberculosis H37Rv was treated with INH (7 μM, 20× MIC), vitamin C (1 or 4 mM) and a combination of INH and vitamin C (1 and 4 mM). (c) mc24997, a RIF- and INH-resistant M. tuberculosis H37Rv strain was treated with vitamin C (4 mM). (d) Vitamin C (4 mM) was added to a drug-susceptible strain (V9124) and to an extensively drug-resistant strain (TF275) of M. tuberculosis from the Kwa-Zulu Natal province of South Africa. Growth was followed and CFUs were determined by plating 10- fold serial dilutions and incubating the plates at 37°C for 4 weeks. The experiments were done at leas t in triplicate and the average with standard deviation is plotted. Vilchèze C, Hartman T, Weinrick B, Jacobs WR. Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction. Nat Commun 2013;4:1881. doi:10.1038/ncomms2898.

Figure 2 -

A model of innate receptor signaling in mediating TB-IRIS pathogenesis. Microarray profiling revealed that TLR signaling and inflammasome activation are critical in mediating TB-IRIS pathogenesis. Our proposed model begins with M. tuberculosis antigen recognition by surface-expressing TLRs, which triggers the downstream signaling cascade with adaptor molecules such as MyD88 and IRAK4 to activate IRF7, thereby triggering the production of type I IFN. Paracrine signaling of Type I IFN to IFNAR recruits and phosphorylates STAT1/2 dimers, leading to further recruitment of IRF9 and the formation of ISGF3, thereby inducing pro-caspase-11 (caspase-4/5 in human) and AIM-2 inflammasome (caspase-1). Caspase-11 cleaves IL-1α into its mature form and can lead to pyroptosis. The noncanonical inflammasome (caspase-11) can also activate the canonical inflammasome (caspase-1), which cleaves IL-1β and IL-18 into their mature form. Alternatively, TLR signaling via MyD88 can also activate NF-κb via the TAK1/IKK complex. Activation of NF-κb triggers the production of an array of cytokines, including TNF-α, IL-6 and IL-12. In addition, NF-κb can also activates NLRP1/3 inflammasomes and subsequently leads to the production of IL-1β and IL-18. Lai RPJ, Meintjes G, Wilkinson RJ. HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome. Semin Immunopathol 2016;38:185–98. doi:10.1007/s00281-015-0532-2.

Figure 3 -

Current TB drug pipeline (http://www.newtbdrugs.org/pipeline.php, accessed on July 7^th, 2016)

Figure 4 -

INDIGO takes in known drug-interaction and chemogenomics data in model organisms (E. coli), and enables large-scale prediction of drug interaction outcomes. By analyzing the evolutionary conservation of genes identified by INDIGO to be predictive of drug interactions in E. coli, we successfully predicted drug synergy and antagonism in the bacterial pathogens Mycobacterium tuberculosis and Staphylococcus aureus.

Figure 5 -

Current TB vaccine pipeline (information self-reported by vaccine sponsors to AERAS, last revised on December 17^th, 2015)