Computational modeling of tuberculous meningitis reveals an important role for tumor necrosis

Abstract

Tuberculosis is a global health issue with annually about 1.5 million deaths and 2 billion infected people worldwide. Extra pulmonary tuberculosis comprises 13% of all cases of which tuberculous meningitis is the most severe. It has a high mortality and is often diagnosed once irreversible neurological damage has already occurred. Development of diagnostic and treatment strategies requires a thorough understanding of the pathogenesis of tuberculous meningitis. This disease is characterized by the formation of a cerebral granuloma, which is a collection of immune cells that attempt to immunologically restrain, and physically contain bacteria. The cytokine tumor necrosis factor-α is known for its important role in granuloma formation. Because traditional experimental animal studies exploring tuberculous meningitis are difficult and expensive, another approach is needed to begin to address this important and significant disease outcome. Here, we present an in silico model capturing the unique immunological environment of the brain that allows us to study the key mechanisms driving granuloma formation in time. Uncertainty and sensitivity analysis reveal a dose-dependent effect of tumor necrosis factor-α on bacterial load and immune cell numbers thereby influencing the onset of tuberculous meningitis. Insufficient levels result in bacterial overgrowth, whereas high levels lead to uncontrolled inflammation being detrimental to the host. These findings have important implications for the development of immuno-modulating treatment strategies for tuberculous meningitis.

Immunological recovery in patients with pulmonary tuberculosis after intensive phase treatment

“… 33 Previous studies have shown that excessive TNF-α levels cause damage to the immune pathological response in cells and to protection of the body’s defense. 34 – 36 TNF-α levels may be related to the severity of the disease process and may serve as a parameter for predicting the prognosis of pulmonary TB.…”

A hypothetical astrocyte–microglia lactate shuttle derived from a 1H NMR metabolomics analysis of cerebrospinal fluid from a cohort of South African children with tuberculous meningitis

“…Infection of the Mtb bacilli occurs through inhalation of aerosolized droplets and harbouring of the bacilli in the pulmonary system. Should dissemination into the lympho-hematogenous circulatory system occur (Krishnan et al 2010 ; El-Kebir et al 2013 ), the brain becomes a very attractive site for the establishment of metastatic foci due its rich vascular and oxygen supply. Mtb appears to enter the subarachnoid space via rupture of an adjacent parenchymal tubercle (Leonard and Des Prez 1990 ) and CD14 receptors of the microglia may render them as the principal cell target in the CNS (Peterson et al 1995 ).…”

Predictors of fever response in tuberculous meningitis: A clinical, MRI and biomarker study

“…TNF‐α gene expression and TNF‐α concentration in the CSF were higher in those with severe meningitis, infarction, hydrocephalous and exudates on MRI, and death, which also suggests a relationship of bacterial load leading to more severe meningitis, MRI changes, longer duration of fever and death. TNF‐α activates macrophages, recruits inflammatory cells, induces chemokine production and enhances apoptosis, which may explain the association of TNF‐α gene expression with clinical and MRI changes 33,34 . The association of elevated TNF‐α in lumbar and ventricular CSF and infarction has been reported in earlier studies 35,36 .…”