Proresolving mediator profiles in cerebrospinal fluid are linked with disease severity and outcome in adults with tuberculous meningitis

摘要

Tuberculous meningitis (TBM) is the most lethal form of tuberculosis infection, characterized by a dysregulated immune response that frequently leads to neurologic injury and death despite the best available treatment. The mechanisms driving the inflammatory response in TBM are not well understood. To gain insights into these mechanisms, we used a lipid mediator-profiling approach to investigate the regulation of a novel group of host protective mediators, termed specialized proresolving mediators (SPMs), in the cerebrospinal fluid (CSF) of adults with TBM. Herein, using CSF from patients enrolled into a randomized placebo-controlled trial of adjunctive aspirin treatment, we found distinct lipid mediator profiles with increasing disease severity. These changes were linked with an up-regulation of inflammatory eicosanoids in patients with severe TBM and a decrease in the production of a number of SPMs. CSF proresolving mediator concentrations were also associated with 80-d survival. In survivors, we found a significant increase in proresolving mediator concentrations, including the lipoxygenase 5-derived 13-series resolvin (RvT)2, RvT4, and 15-epi-lipoxin B-4, compared with those who died. Of note, treatment of patients with high-dose aspirin led to a decrease in the concentrations of the prothrombic mediator thromboxane A(2), reduced brain infarcts, and decreased death in patients with TBM. Together, these findings identify a CSF SPM signature that is associated with disease severity and 80-d mortality in TBM.