Mutong Fang

This study aimed to map the cerebrospinal fluid (CSF) molecular landscape across distinct stages of tuberculosis progression and to identify multi-omics signatures associated with tuberculous meningitis (TBM). Integrated proteomic and metabolomic profiling of CSF from 17 patients representing three disease stages: pulmonary tuberculosis (TB), hematogenous disseminated tuberculosis (HDTB), and disseminated tuberculosis with concomitant tuberculous meningitis (HDTB+TBM) were performed. Quantitative proteomics and non-targeted metabolomics were combined with pathway enrichment and network-based analyses to delineate stage-specific molecular alterations. CSF multi-omics profiling revealed modest molecular changes between TB and HDTB, but a marked and coordinated remodeling during the transition from HDTB to TBM. Compared with the HDTB+TBM group, the TB group exhibited 546 upregulated and 410 downregulated proteins, together with 80 differentially abundant metabolites. Integrated analyses converged on glycolysis/gluconeogenesis, pentose phosphate metabolism, and extensive O- and N-glycan biosynthesis pathways, indicating coupled metabolic and glycosylation rewiring during meningeal involvement. Six proteins (ENO2, LDHB, GALNT7, MAN1C1, PGD, and B4GALT1) emerged as a biologically coherent signature distinguishing TBM from non-meningeal tuberculosis. This study maps the molecular trajectory from tuberculosis to disseminated disease and tuberculous meningitis, identifying TBM as a distinct neuro-immune-metabolic state and providing a framework for mechanism-informed biomarker development.

Background: The morbidity of rifampicin/multidrug-resistant tuberculous meningitis (RR/MDR-TBM) has shown an increasing trend globally. Its mortality rate is significantly higher than that of non-rifampicin/multidrug-resistant tuberculous meningitis (NRR/MDR-TBM). This article aimed to explore risk factors related to RR/MDR-TBM, and compare therapeutic effects of linezolid (LZD)- and non-linezolid-containing regimen for RR/MDR-TB patients in Shenzhen city. Furthermore, we aimed to find a better therapy for pathogen-negative TBM with RR/MDR-TBM related risk factors. Methods: We conducted a retrospective study enrolling 137 hospitalized cases with confirmed TBM from June 2014 to March 2020. All patients were divided into RR/MDR-TBM group (12 cases) and NRR/MDR-TBM group (125 cases) based on GeneXpert MTB/RIF and (or) phenotypic drug susceptibility test results using cerebral spinal fluid (CSF). The risk factors related to RR/MDR-TBM were investigated through comparing clinical and examination features between the two groups. The mortality rate of RR/MDR-TBM patients treated with different regimens was analyzed to compare their respective therapeutic effects. A difference of P < 0.05 was considered statistically significant. Results: Most patients (111/137, 81%) were from southern or southwestern China, and a large proportion (72/137, 52.55%) belonged to migrant workers. 12 cases were RR/MDR-TBM (12/137, 8.8%) while 125 cases were NRR/MDR-TBM (125/137, 91.2%). The proportion of patients having prior TB treatment history in the RR/MDR-TBM group was significantly higher than that of the NRR/MDR-TBM group (6/12 vs. 12/125, 50% vs. 10.5%, P < 0.01). No significant difference was observed on other clinical and examination features between the two groups. Mortality was significantly lower in RR/MDR-TBM patients on linezolid-containing treatment regimen than those who were not (0/7 versus 3/5, 0% versus 60%, P = 0.045). Conclusions: The main related risk factor of RR/MDR-TBM is the history of anti-tuberculosis treatment. Linezolid-containing regimen appears to lower mortality rate of RR/MDR-TBM significantly in our study. We think Linezolid should be evaluated prospectively in the treatment of RR/MDR-TBM.