Book Description

TB of the central nervous system (CNSTB) is the most devastating form of the disease worldwide. Tuberculosis meningitis (TBM), the most severe manifestation of CNSTB has been shown to lead to endovasculitis, permanent neurologic damage, cerebral ischemia and high mortality. First characterized in 1933, TBM is claimed to be the result of bacteremia after pulmonary infection leading to hematogenous dissemination and seeding of bacteria in the brain parenchyma or meninges. Yet, mechanistic knowledge determining how the non-motile Mycobacteria tuberculosis (Mtb) escape the primary infection leading to bacteremia and how once it reaches the CNS can traverse the highly complex and restrictive blood-brain barrier (BBB) is incomplete. This thesis work demonstrates the development of a novel in vitro primary cell co-culture BBB/ mycobacterium granuloma system used to investigate the interactions between Mtb-infected immunity and BBB endothelium. Here, we show mycobacterium infection impede DC migration but enhance DC-mediated recruitment of immune cells leading to formation of granulomatous-like structures on brain microvessel endothelium. These structures are similar to pulmonary granulomas in cell composition and in part function as well as being dependent on TNF-a for establishment. Clusters induce vascular inflammation on the brain endothelium leading to increased adhesion molecules (ICAM-1 and VCAM-1), disorganization of tight junction and tight junction-associated proteins claudin-5 (Cldn-5) and zonula occludens-1 (ZO-1), respectively as well as cellular stress indicators in disorganized mitochondrial networks and cluster associated damage (CAD) together suggesting barrier integrity loss. Inhibition of both TNF-a and matrix metalloproteinases (MMPs) reduced CAD indicating barrier damage is achieved through pro-inflammatory factor secretion after cluster formation. This loss in barrier integrity provides multiple opportunities for infected cell carriers to transport Mtb across the BBB demonstrating for the first time 3 important pathologies associated with TBM. 1) It provides a mechanism for cell-mediated dissemination of Mtb into the CNS through destruction of brain microvessel endothelium, 2) a possible explanation of events preceding hematogenous dissemination from primary pulmonary infections breaching systemic or pulmonary vasculature, and 3) cluster formation in microvasculature may play a role in the obstruction of blood flow leading to high incidences of ischemic stroke in TBM patients.