Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone

Abstract

Adjunctive treatment with antiinflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant in Leukotriene A4 Hydrolase (LTA4H), which regulates expression of the proinflammatory mediator leukotriene B4 (LTB4). TT homozygotes, with increased expression of LTA4H, have the highest survival when treated with dexamethasone and the lowest survival without. While the T allele is present in only a minority of the world’s population, corticosteroids confer modest survival benefit worldwide. Using Bayesian methods, we examined how pretreatment levels of cerebrospinal fluid proinflammatory cytokines affect survival in dexamethasone-treated tuberculous meningitis. LTA4H TT homozygosity was associated with global cytokine increases, including tumor necrosis factor. Association between higher cytokine levels and survival extended to non-TT patients, suggesting that other genetic variants may also induce dexamethasone-responsive pathological inflammation. These findings warrant studies that tailor dexamethasone therapy to pretreatment cerebrospinal fluid cytokine concentrations, while searching for additional genetic loci shaping the inflammatory milieu.

Shooting yourself in the foot: How immune cells induce antibiotic tolerance in microbial pathogens

“…We also recently showed that Tempol, a superoxide dismutase mimetic and potent antioxidant, improved antibiotic efficacy in a systemic S. aureus infection [6]. However, differences in host genetics may profoundly affect the success of immunomodulatory strategies [34].…”

Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport

“…These findings implicated LTB4 and TNF-induced inflammation in mortality ( 3 , 4 , 10 ). Moreover, high TNF levels were associated with mortality even among individuals without the high LTA4H-expressing variant suggesting that TNF excess, resulting from diverse host genetic determinants, is a far-reaching host susceptibility factor in TB ( 3 ). Consistent with these findings, necrotic human tuberculous granulomas have more TNF than non-necrotic ones ( 11 ).…”

“…Tumor necrosis factor (TNF) is both a host resistance and susceptibility factor in tuberculosis (TB) ( 1 – 3 ). Findings in the genetically tractable and optically transparent zebrafish larva infected with Mycobacterium marinum (Mm) have revealed the mechanisms behind this dual effect ( 4 – 6 ).…”

“…These zebrafish studies led to the identification of a common, functional human LTA4H variant associated with mortality from tuberculous meningitis, the severest form of TB ( 4 , 10 ). In cohorts in Vietnam and Indonesia, the high LTA4H-expressing variant was associated with increased cerebrospinal fluid TNF levels and increased mortality that was mitigated by adjunctive treatment with corticosteroids, broadly acting immunosuppressants ( 3 , 4 , 10 ). These findings implicated LTB4 and TNF-induced inflammation in mortality ( 3 , 4 , 10 ).…”

mTOR-regulated Mitochondrial Metabolism Limits Mycobacterium-induced Cytotoxicity

“…The use of unbiased genetic screens and candidate gene approaches in zebrafish larvae has shed light on granuloma biology (Ramakrishnan, 2013; 2020). In particular, hypersusceptible zebrafish mutants displaying accelerated granuloma necrosis have identified innate immune host determinants that protect against necrosis and that are relevant in the context of human TB (Berg et al, 2016; Clay et al, 2008; Pagan et al, 2015; Roca and Ramakrishnan, 2013; Roca et al, 2019; Tobin et al, 2012; Tobin et al, 2010; Whitworth et al, 2021a; Whitworth et al, 2021b).…”