Development and Investigation of a rabbit model of tuberculosis tissue destruction

Abstract

Tuberculosis kills more people than any other bacterial disease. The characteristic tissue destruction that occurs during infection contributes to morbidity, mortality, and transmission. Tissue damage limits antibiotic effectiveness, and generates regions of immune privilege. Therefore, therapies that target tissue destruction may improve treatment outcomes.

Currently, modelling tissue destruction in vivo requires the infection of large animals for prolonged periods. These models are highly variable in outcome. This makes experimentation challenging, and limits there use in testing therapeutic strategies, which in turn limits the progression of potential therapies to clinical trials.

This thesis outlines the development of a highly consistent rabbit model of cavitary tuberculosis, in which novel therapies can be investigated, using small groups of animals. A method to assess pathology in vivo by breath-hold computed tomography was also developed. Matrix metalloproteinase-1 is confirmed as a potential mediator of tissue destruction, and cathepsin K is newly identified as a potential mediator of tissue destruction. These collagenases are targetable with the drugs Cipemastat and Odanacatib respectively, both of which are safe in man.

This thesis provides a novel system for trialling treatments for tuberculosis in the context of human-like, tissue-destructive pathology. This may facilitate the selection of both antibiotic and non-antibiotic treatment strategies for tuberculosis. This model will allow for a better understanding of the physical, chemical, molecular, genetic and immunological characteristics and determinants of cavitary tuberculosis.