Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis

Abstract

29Tuberculous meningitis (TBM) is the most lethal form of tuberculosis infection, 30 characterized by a dysregulated immune response that frequently leads to 31 neurological injury and death despite the best available treatment. The mechanisms 32 driving the inflammatory response in TBM are not well understood. To gain insights 33 into these mechanisms we used a lipid mediator profiling approach to investigate the 34 regulation of a novel group of host protective mediators, termed specialized pro-35 resolving mediators (SPM), in the cerebrospinal fluid (CSF) of adults with TBM 36 enrolled into a randomised placebo-controlled trial of adjunctive aspirin treatment. 37We found distinct lipid mediator profiles with increasing disease severity, changes 38 that were linked with an upregulation of inflammatory eicosanoids in patients with 39 severe TBM and a decrease in the production of a number of 5-lipoxygenase 40 (ALOX5)-derived SPM. CSF pro-resolving mediator concentrations were also 41 associated with 80-day survival. In survivors, we found a significant increase in pro-42 resolving mediator concentrations, including the ALOX5-derived resolvin (Rv)T2, 43RvT4 and 15-epi-Lipoxin (LX)B4, compared to those who died. Aspirin administration 44 increased the ratio of pro-resolving to pro-inflammatory mediators decreasing the 45 concentrations of the prothrombic mediator TxA2, changes that were linked with early 46 reductions in brain infarcts and deaths. Together, these findings identify a CSF SPM 47 signature that is associated with disease severity and 80-day mortality in TBM. 48Furthermore, the therapeutic manipulation of the ratio between pro-resolving 49 mediators and pro-inflammatory/thrombogenic mediators in the CSF, by aspirin for 50 example, offers a novel treatment strategy to reduce the morbidity and mortality 51 caused by TBM. Authors Summary 54Infections of the brain and the meninges by Mycobacterium tuberculosis (M. tb) lead 55 to severe inflammation and are associated with poor outcomes. The mechanisms 56 leading to this disease remain poorly defined. Herein, we investigated how M. tb 57 infection regulates the concentrations of specialized pro-resolving mediators that are 58 central in controlling the body's ability to clear infections. In these investigations, we 59 found that disease survival was linked with increased concentrations of a number of 60 these protective molecules including resolvins and lipoxins. Treatment of M. tb-61 infected patients with aspirin decreased the production of the immunosuppressive 62 and thrombogenic mediator thromboxane A2 improving the balance between 63 protective and inflammatory molecules. Of note, these changes were linked with 64 reduced disease severity and improved survival. Therefore, the present findings 65 suggest a previously unappreciated role for pro-resolving mediators in TBM 66 pathogenesis.67 90 mediate the protective actions of several widely used therapeutics, including 91 atorvastatin, pravastatin and aspirin (7, 12, 13). 92We recently tested the hypot...