Experimental study of tuberculosis: From animal models to complex cell systems and organoids

Abstract

Tuberculosis (TB) is a devastating disease to mankind that has killed more people than any other infectious disease. Despite many efforts and successes from the scientific and health communities, the prospect of TB elimination remains distant. On the one hand, sustainable public health programs with affordable and broad implementation of anti-TB measures are needed. On the other hand, achieving TB elimination requires critical advances in three areas: vaccination, diagnosis, and treatment. It is also well accepted that succeeding in advancing these areas requires a deeper knowledge of host-pathogen interactions during infection, and for that, better experimental models are needed. Here, we review the potential and limitations of different experimental approaches used in TB research, focusing on animal and human-based cell culture models. We highlight the most recent advances in developing in vitro 3D models and introduce the potential of lung organoids as a new tool to study Mycobacterium tuberculosis infection.

Fig 1. An integrative view on the experimental models for tuberculosis (TB) research.

Questions arising from clinical, genetic, and epidemiological data on TB are addressed using a variety of experimental approaches. The traditional approach has used a combination of 2D culture systems and animal models. The recent development of 3D cell culture systems composed by multiple cell types provides in vitro models with a level of complexity previously only available in vivo. The generation of lung-on-chip cultures and the possibility of generating lung organoids from healthy or patient donors may in future offer experimental systems closer to the human pathophysiology. Abbreviations: ESC, embryonic stem cells; iPSC, induced pluripotent stem cells; PSC, pluripotent stem cells.

Fig 2. Proportion of different animal models in TB research.

Pie chart illustrating the percentage of publications for each of the most commonly used animal models in TB research. Results from a Pubmed search performed on 9 February 2017 using the following key words: “mouse AND tuberculosis,” “guinea pig AND tuberculosis,” “rabbit AND tuberculosis,” “non-human primate AND tuberculosis,” and “zebra fish AND tuberculosis.” Percentages were calculated based on the total number of publications for all animal models.

Fig 3. Use of 3D systems in TB research.

Graph illustrating the increasing number of publications using 3D models for TB research between January 2000 and February 2017, every 3 years. Results are from a Pubmed search performed on 14 February 2017 using the keywords “3D models AND tuberculosis”.