Proteomic Analysis of Serum and Cerebrospinal Fluid in Children with Encephalopathy Associated with Human Betaherpesvirus 6B

TL;DR

This study uses proteomic analysis to compare serum and cerebrospinal fluid proteins in children with HHV-6B-related encephalopathy to understand the disease's pathogenesis.

Contribution

The study identifies specific proteins and metabolic pathways associated with severe neurological complications of HHV-6B infection.

Findings

Nineteen serum proteins were differentially expressed in AESD compared to cFS during the acute phase.

The glycolytic pathway was upregulated in AESD, and MARCKS and GOLM1 were validated as upregulated proteins.

CSF analysis revealed 38 differentially expressed proteins, with cholesteryl ester transfer protein upregulated in AESD.

Abstract

Exanthem subitum (ES), a benign febrile exanthematous disease, is caused by primary human betaherpesvirus 6B (HHV-6B) infection. It may cause neurological complications, including complex febrile seizures (cFS), acute encephalopathy with biphasic seizures, and late reduced diffusion (AESD). cFS resolves spontaneously; however, AESD can pose severe sequelae. We aimed to elucidate AESD pathogenesis using a proteomic analysis.

Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), serum and cerebrospinal fluid (CSF) protein profiles were compared between patients with AESD and those with cFS (n = 3 or 4 per group). Metascape was used for enrichment analysis, and the selected proteins were validated using a large sample via enzyme-linked immunosorbent assay (ELISA).

A total of 698 proteins were identified across all serum and CSF samples using LC-MS/MS. Nineteen serum proteins were differentially expressed in AESD and cFS during the acute phase. The glycolytic pathway was upregulated in AESD. Myristoylated alanine-rich C kinase substrate (MARCKS) and Golgi membrane protein 1 (GOLM1) were selected for validation using ELISA. Both proteins were upregulated during the acute phase (n = 11) compared with the convalescent phase (n = 21) in AESD (MARCKS, P = .016; GOLM1, P < .001). MARCKS during the acute phase was also upregulated in AESD compared with that in uncomplicated ES (n = 15) (P = .015). In CSF, 38 proteins were differentially expressed between AESD and cFS during the acute phase. Cholesteryl ester transfer protein in the CSF of patients with AESD was upregulated; however, this could not be validated using ELISA.

Glycolysis and MARCKS pathways might be involved in HHV-6B-associated AESD pathogenesis.

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