Advanced cellular systems to study tuberculosis treatment

Abstract

Mycobacterium tuberculosis (Mtb) kills more humans than any other infection and drug resistant strains are progressively emerging. Whilst the successful development of new agents for multi-drug resistant Mtb represents a major step forward, this progress must be balanced against recent disappointments in treatment-shortening trials. Consequently, there is a pressing need to strengthen the pipeline of drugs to treat tuberculosis (TB) and develop innovative therapeutic regimes. Approaches that bridge diverse disciplines are likely to be required to provide systems that address the limitations of current experimental models. Mtb is an obligate human pathogen that has undergone extensive co-evolution, resulting in a complex interplay between the host and pathogen. This chronic interaction involves multiple micro-environments, which may underlie some of the challenges in developing new drugs. The authors propose that advanced cell culture models of TB are likely to be an important addition to the experimental armamentarium in developing new approaches to TB, and here we review recent progress in this area and discuss the principal challenges.

Three-Dimensional Culture Modelling Reveals Divergent Mycobacterium tuberculosis Virulence and Antimicrobial Treatment Response

“…The coadministration of verapamil increases the efficacy of bedaquiline and delamanid, and this effect is most pronounced for clinical strains. Our findings further highlight the importance of including diverse strains in drug discovery studies [7,8,51,52], while supporting the utility of advanced cell culture models incorporating human cells to refine the drug discovery pipeline [47,53].…”

“…Consequently, better in vitro systems are required for TB drug discovery [47,48]. This problem is illustrated by pyrazinamide, which would not have been identified through a traditional strategy; PZA is not bactericidal under standard culture conditions and works optimally under hypoxic conditions at pH 5.5 [49].…”

Mycobacterium tuberculosisinfection of host cells in space and time

“…Another aspect to consider is that biology is in three dimensions. The relevance of 3-dimensional organisation in the context of Mtb infection and granuloma formation is key to our understanding of TB pathogenesis and 3-dimensional cellular systems have been developed for studying TB treatment (Bielecka and Elkington 2018). In these models, infected primary human cells are co-cultured with collagen matrix gels, agarose beads or agarose-coated plates and it could also include epithelial cells and fibroblasts (Fonseca et al .…”

Modelling early events in Mycobacterium bovis infection using a co-culture model of the bovine alveolus

“…Current knowledge of early events in the pathogenesis of TB have been gained by use of live animal models and a limited number of in vitro monolayer and co-culture models. For the most part, these have been human focussed 28 – 34 . As the innate immune response differs between species and/or the strain of mycobacteria under study 35 , models of each key target species would be beneficial.…”

“…A few in vitro models have been developed with particular emphasis on epithelial and endothelial co-culture at air–liquid interface with the aim of mimicking the alveolar-capillary barrier by close juxtaposition of these two cell types. Such models are reported to more accurately recapitulate the architecture of the distal lung epithelium 28 and better reflect cell behaviours in the in vivo environment compared to two-dimensional monolayers on plastic surfaces under submerged conditions 28 , 30 . For example, Birkness et al .…”