The rabbit model: Pathological manifestations of tuberculous meningitis

In humans, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is transmitted primarily through inhalation of infectious droplets released from patients with symptomatic active TB. Although the bacteria initially lodge into the lungs, they can disseminate by infected lung macrophages and dendritic cells to the lymph nodes, brain, gastrointestinal tract, and reproductive tract, resulting in disseminated extrapulmonary disease. The Mtb-infected macrophages can traverse the blood–brain barrier (BBB) through the Trojan horse mechanism, facilitating bacterial dissemination that can lead to tuberculous meningitis (TBM). In the brain, Mtb infection causes sub-ependymal thickening called Rich-foci, which triggers an inflammatory response that leads to the infiltration of inflammatory cells. Further, inflammatory lesions in the meninges cause vasculitis and blood flow interference, leading to hydrocephalus. The lesions can also cause exudation into the adjacent central nervous system (CNS) structures, including the nerve roots emanating from the brain, resulting in severe neurological abnormalities. While modeling TBM in an animal model is challenging, the rabbit has evolved as a reproducible and reliable experimental system for human TBM. This chapter focuses on the pathological features of the rabbit model TBM. We discuss the methodologies used to establish TBM and examples of the utility of the rabbit model as a preclinical tool for TBM drug development.