Model systems to study Mycobacterium tuberculosis infections: an overview of scientific potential and impediments

Abstract

Despite years of global efforts to combat tuberculosis (TB), Mycobacterium tuberculosis (Mtb), the causative agent of this disease, continues to haunt the humankind making TB elimination a distant task. To comprehend the pathogenic nuances of this organism, various in vitro, ex vivo and in vivo experimental models have been employed by researchers. This review focuses on the salient features as well as pros and cons of various model systems employed for TB research. In vitro and ex vivo macrophage infection models have been extensively used for studying Mtb physiology. Animal models have provided us with great wealth of information and have immensely contributed to the understanding of TB pathogenesis and host responses during infection. Additionally, they have been used for evaluation of anti-mycobacterial drug therapy as well as for determining the efficacy of potential vaccine candidates. Advancements in various 'omics' based approaches have enhanced our understanding about the host-pathogen interface. Although animal models have been the cornerstone to TB research, none of them is ideal that gives us a complete picture of human infection, disease and progression. Further, the review also discusses about the newer systems including three dimensional (3D)-tissue models, lung-on-chip infection model, in vitro TB granuloma model and their limitations for studying TB. Thus, converging information gained from various in vitro and ex vivo models in tandem with in vivo experiments will ultimately bridge the gap that exists in understanding human TB.

Keywords: animal models; cellular models; host-pathogen interactions; omics-based approaches; tuberculosis.

Figure 1

A wide spectrum of clinical fates of Mtb infection: Alveolar macrophages are the first cells to get exposed to Mtb and hence are the most important line of defense that decides the fate of the infection. Many individuals do not get infected with Mtb, due to the robust innate immunity that leads to an efficient activation of macrophages, resulting in a stronger anti-mycobacterial response and elimination of the pathogen. However, most of the individuals who get infected with Mtb enter into latency (Latent TB) and an effective adaptive response is able to control the infection in a few intact granulomas consisting of various immune cells that act as safeguards to contain the infection. With a successful adaptive response, some latent individuals also sterilize the infection via calcification. Some 5-10% of infected individuals develop active TB with cavitary pulmonary tuberculosis becoming a potential source of transmitting the pathogen to other uninfected individuals. In addition, ~ 90% of the active TB cases are results of reactivation of latent infections, due to the immune comprised status (HIV infection, anti-TNF-α therapies) of these individuals and thus, with inadequate immune responses, granulomas become necrotic with a caseous center (soft, cheese-like appearance), which results in dissemination of the infection to other parts of the host system. The figure is prepared by using BioRender.com.

Figure 2

Multiple omics-based approaches to understand disease biology: Various tissue samples can be collected to isolate different biological molecules (DNA, RNA, metabolites, proteins and lipids) from animals. These tissue samples can be processed and subjected to mass spectrometry or NGS platforms to perform various omics-based approaches, such as proteomics, metabolomics, lipidomics, genomics, transcriptomics, epigenomics, respectively. Analysis of the omics data allow us to compare the differences between the disease progression and characteristics of healthy vs diseased or treated vs untreated tissue samples. Moreover, integration of multi-omics data would help us in understanding the complete spectrum of the disease, allowing the discovery of therapeutic targets and disease-biomarkers. The figure is prepared by using BioRender.com.