Investigating tuberculosis by engineering human granulomas

Lead Research Organisation: University of Southampton
Department Name: Clinical and Experimental Sciences

Abstract

Tuberculosis continues to kill almost 2 million people per year worldwide and is becoming increasingly resistant to the drug therapy, because treatment has remained unchanged for over 30 years. Tuberculosis research relies heavily on animal studies, but these are simply not the same as disease in patients. We will develop an entirely new way of studying tuberculosis infection by using human cells and the tuberculosis bacteria sprayed into tiny balls incorporating fibres that support the human lung. We will use this model to study how the body responds to tuberculosis infection and investigate new treatments which may reduce the lung damage in patients with tuberculosis and also speed up the killing of the bacteria. This approach will replace the need for extensive screening experiments in laboratory animals and accelerate the development of new treatments which are urgently needed. The approach will also be valid to investigate other human diseases by using cells in culture to model the complex 3-dimensional interactions that happen in patients, and so has the potential to replace animal experiments used to study a wide array of human diseases.

Technical Summary

Tuberculosis (TB) remains a global health pandemic but treatment has remained unchanged for over 30 years. TB research relies extensively on animal studies, including mice, guinea pigs, rabbits and non-human primates, but no model accurately reflects disease in man. We have recently identified matrix metalloproteinases (MMPs) as critical drives of immunopathology in TB and have shown that matrix destruction is a key step leading to TB immunopathology. In this fellowship, I will develop an in vitro granuloma model of TB infection by exploiting bioelectrospray technology to generate spheroids incorporating primary human cells, Mycobacterium tuberculosis (Mtb) and extracellular matrix components. I will determine the effect of different spheroid matrix composition on granuloma formation and MMP and cytokine production. Next, I will investigate regulation of intracellular signalling pathways and mycobacterial growth by the extracellular matrix, and incorporate divergent Mtb lineages and cells from patients with TB. Finally, I will develop the model to screen for new antimycobacterial compounds active within a granuloma and also to assess efficacy of vaccination strategies ex vivo from patients. These studies will dissect TB immunopathology in an entirely novel in vitro system to identify new therapeutic candidates and evaluate vaccine responses, replacing the need for extensive studies in suboptimal animal models. The 3-dimensional cell culture platform will also be applicable to other human diseases where cell-cell and cell-matrix interactions are important, and so has the potential to replace animal modelling in a wide range of diseases.

Publications

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