Proteomic Analysis of Cerebrospinal Fluid in Children with Acute Enterovirus-Associated Meningoencephalitis Identifies Dysregulated Host Processes and Potential Biomarkers

Enteroviruses (EVs) are major causes of viral meningoencephalitis in children. To better understand the pathogenesis and identify potential biomarkers, cerebrospinal fluid proteome in children ( n = 52) suffering from EV meningoencephalitis was compared to that in EV-negative control subjects ( n = 53) using the BoxCar acquisition technique. Among 1697 proteins identified, 1193 with robust assay readouts were used for quantitative analyses. Differential expression analyses identified 154 upregulated and 227 downregulated proteins in the EV-positive group. Functional analyses showed that the upregulated proteins are mainly related to activities of lymphocytes and cytokines, inflammation, and responses to stress and viral invasion, while the downregulated proteins are mainly related to neuronal integrity and activity as well as neurogenesis. According to receiver operating characteristic analysis results, Rho-GDP-dissociation inhibitor 2 exhibited the highest sensitivity (96.2%) and specificity (100%) for discriminating EV-positive from EV-negative patients. The chemokine CXCL10 was most upregulated (>300-fold) with also high sensitivity (92.3%) and specificity (94.3%) for indicating EV positivity. Thus, this study uncovered perturbations of multiple host processes due to EV meningoencephalitis, especially the general trend of enhanced immune responses but impaired neuronal functions. The identified dysregulated proteins may also prompt biomarker development.