Marked IDO2 expression and activity related to autophagy and apoptosis in brain tissue of fatal tuberculous meningitis.

In about 1% of tuberculosis (TB) patients, Mycobacterium tuberculosis (M. tuberculosis) can disseminate to the meninges, causing tuberculous meningitis (TBM) with mortality rate up to 60%. Chronic granulomatous inflammation (non-necrotizing and necrotizing) in the brain is the histological hallmark of TBM. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and the generated kynurenine metabolites exert major effector functions relevant to TB granuloma functioning. Here we have assessed immunohistochemically IDO1 expression and activity and its effector function and that of its isoform, IDO2, in post-mortem brain tissue of patients that demised with neurotuberculosis. We also related these findings to brain tissue of fatal/severe COVID-19. In this study, IDO1 and IDO2 were abundantly expressed and active in tuberculoid granulomas and were associated with the presence of M. tuberculosis as well as markers of autophagy and apoptosis. Like in fatal/severe COVID-19, IDO2 was also prominent in specific brain regions, such as the inferior olivary nucleus of medulla oblongata and cerebellum, but not associated with granulomas or with M. tuberculosis. Spatially associated apoptosis was observed in TBM, whereas in fatal COVID-19 autophagy dominated. Together, our findings highlight IDO2 as a potentially relevant effector enzyme in TBM, which may relate to the symptomology of TBM.

The use of thalidomide to treat children with tuberculosis meningitis: A review.

Much of the morbidity and mortality caused by tuberculous meningitis (TBM) is mediated by a dysregulated immune response. Effective host-directed therapy is therefore critical to improve survival and clinical outcomes. Currently only one host-directed therapy (HDT), corticosteroids, is proven to improve mortality. However, there is no evidence that corticosteroids reduce morbidity and the mechanism of action for mortality reduction is uncertain. Further, it has no proven benefit in HIV co-infected individuals. One promising host-directed therapy approach is to restrict the immunopathology arising from tumour necrosis factor (TNF)-α excess is via TNF-α inhibitors. There are accumulating data on the role of thalidomide, anti-TNF-α monoclonal antibodies (infliximab, adalimumab) and the soluble TNF-α receptor (etanercept) in TBM treatment. Thalidomide was developed nearly seventy years ago and has been a highly controversial drug. Birth defects and toxic adverse effects have limited its use but an improved understanding of its immunological mechanism of action suggest that it may have a crucial role in regulating the destructive host response seen in inflammatory conditions such as TBM. Observational studies at our institution found low dosage adjunctive thalidomide safe in treating tuberculous mass lesions and blindness related to optochiasmatic arachnoiditis, with good clinical and radiological response. In this review, we discuss possible mechanisms of action for thalidomide, based on our clinico-radiologic experience and post-mortem histopathological work. We also propose a rationale for its use in the treatment of certain TBM-related complications.

The immunological architecture of granulomatous inflammation in central nervous system tuberculosis.

Of all tuberculosis (TB) cases, 1% affects the central nervous system (CNS), with a mortality rate of up to 60%. Our aim is to fill the 'key gap' in TBM research by analyzing brain specimens in a unique historical cohort of 84 patients, focusing on granuloma formation. We describe three different types: non-necrotizing, necrotizing gummatous, and necrotizing abscess type granuloma. Our hypothesis is that these different types of granuloma are developmental stages of the same pathological process. All types were present in each patient and were mainly localized in the leptomeninges. Intra-parenchymal granulomas were less abundant than the leptomeningeal ones and mainly located close to the cerebrospinal fluid (subpial and subependymal). We found that most of the intraparenchymal granulomas are an extension of leptomeningeal lesions which is the opposite of the classical Rich focus theory. We present a 3D-model to facilitate further understanding of the topographic relation of granulomas with leptomeninges, brain parenchyma and blood vessels. We describe innate and adaptive immune responses during granuloma formation including the cytokine profiles. We emphasize the presence of leptomeningeal B-cell aggregates as tertiary lymphoid structures. Our study forms a basis for further research in neuroinflammation and infectious diseases of the CNS, especially TB.

Increased occurrence of left-handedness after severe childhood bacterial meningitis: support for the pathological left-handedness hypothesis.

The hypothesis that brain damage during infancy causes pathological left-handedness was tested by assessing handedness in 182 survivors of childhood non-Hemophilus influenza type b bacterial meningitis in the Netherlands (mean age of 9.7 years). These children were selected randomly after clustering them into those with or without parental report on academic and behavioural problems. Medical records were obtained from the hospitals, while handedness and neurodevelopmental outcome were assessed at school age. Logistic regression analysis was used to study the relationship between a severity score of bacterial meningitis and handedness. Fifteen percent were left-handed. Severity of childhood bacterial meningitis was related to left-handedness (Odds ratio (OR) 6.2, 95% confidence interval (CI) 2.0-18.6 for those with a total severity score above the median as compared to those below). Compared to non-left-handed children, left-handed children had lower IQ (mean difference -6.6, 95% CI -12 to -1.2), tended to have lower vocabulary scores on WISC-r (-1.0, -2.1 to 0), and lower Beery scores on visual-motor integration (-4.9, -10.1 to 0.4). Left-handed children also tended to have more combined academic and behavioural limitations (OR 2.7, 95% CI 0.9-8.6), lower manual speed of the dominant hand (mean difference -9 taps, p < 0.05) and better manual steadiness in the non-dominant hand (mean difference of contact's time -2.7 s, p < 0.05). Left-handed post-meningitic children generally have worse neurodevelopmental outcome than non-left-handed survivors. Our results support the role of early life brain damage in left-handedness.