河村 吉紀

Severe acute encephalopathy/encephalitis (AE) associated with SARS-CoV-2 has been increasingly reported since the emergence of the Omicron variant. Several pediatric cases have shown the development of acute fulminant cerebral edema (AFCE) or hemorrhagic shock encephalopathy syndrome (HSES), which are linked to high morbidity and mortality. However, the underlying pathogenic mechanisms remain unclear. We performed single-cell RNA sequencing of peripheral blood mononuclear cells from a pediatric patient with SARS-CoV-2-associated AE presenting with AFCE/HSES and compared the data with those from two patients with mild AE, one patient with febrile seizures due to non-SARS-CoV-2 pathogens, and publicly available pediatric COVID-19 datasets without neurological complications. During the acute phase, we observed a prominent expansion of B-cell populations, including distinct activated B-cell clusters. Cell-cell communication analysis identified macrophage migration inhibitory factor signaling, although it was not specific to SARS-CoV-2-associated AE. Notably, heat shock protein genes, particularly HSPA1A and HSPB1, were selectively upregulated across multiple immune cell types only in severe SARS-CoV-2-associated AE. Enzyme-linked immunosorbent assay confirmed significantly elevated plasma and serum protein levels of HSPA1A and HSPB1 during the acute phase. These findings highlight HSPA1A and HSPB1 as potential biomarkers of severe SARS-CoV-2-associated AE and suggest a pathogenic possible role for stress-response pathways.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: Glycolysis and MARCKS pathways might be involved in HHV-6B-associated AESD pathogenesis.

ABSTRACT Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE‐HS) is an intractable form of epilepsy involving the hippocampus, and temporal lobectomy remains an effective treatment. Human herpesvirus 6B (HHV‐6B) establishes latency in the hippocampus and may contribute to MTLE‐HS pathogenesis by altering host gene expression; however, transcriptomic data from healthy controls remain limited. This study investigated the role of HHV‐6B to MTLE‐HS pathogenesis by analyzing gene expression in resected hippocampal tissues. Samples were collected from 12 to 43 HHV‐6 DNA‐positive and ‐negative patients, respectively, and three controls. RNA sequencing was performed on eight representative samples, followed by RT‐qPCR validation of nine selected genes in 58 samples. RNA sequencing identified 600 differentially expressed genes (210 upregulated, 390 downregulated) between HHV‐6B‐positive MTLE‐HS and controls. Pathway enrichment analysis revealed involvement of synaptic signaling and inflammatory responses, with prostaglandin biosynthesis specifically upregulated in HHV‐6B‐positive tissues. Two genes were significantly upregulated in HHV‐6B‐positive compared with HHV‐6B‐negative samples. RT‐qPCR confirmed elevated cholesterol 25‐hydroxylase and interleukin 1 beta expression in HHV‐6 DNA‐positive samples (both p  = 0.031). These findings suggest that HHV‐6B may contribute to MTLE‐HS pathogenesis by modulating the expression of host inflammatory genes, supporting a role for neuroinflammation and the potential benefits of anti‐inflammatory therapies.

BACKGROUND: Biliary atresia (BA) is a severe infantile hepatobiliary disorder of unknown etiology. Perinatal rotavirus (RV) infection has been implicated in animal models of BA; however, supporting human data remains limited. The study investigated the serological evidence of recent RV infection in infants with BA using RV-specific immunoglobulin (Ig)-A, a marker of primary infection unaffected by maternal antibodies. METHODS: Serum samples from 17 infants with BA and 30 age-matched controls without gastrointestinal symptoms or prior RV vaccination were retrospectively analyzed. Anti-RV-IgA titers were measured by enzyme-linked immunosorbent assay using purified WA-strain virions. Cytomegalovirus (CMV)-IgM and Epstein-Barr virus (EBV)-viral capsid antigen (VCA)-IgM levels were assessed using commercial enzyme immunoassays. RESULTS: RV-IgA was detected in 70.6% (12/17) of the patients with BA versus 3.4% (1/29) of the controls (p < 0.001). RV-IgA titers were significantly higher in the BA group (median: interquartile range 28.0:26.0-210.0) than in the control group (23.5:22.0-24.8) (p = 0.004). Among patients diagnosed with BA after 14 days of age, 84.6% (11/13) were RV-IgA-positive. CMV-IgM was detected in three patients in the BA group and one individual in the control group, while EBV-VCA-IgM was negative in BA patients and positive in two controls; neither difference was statistically significant. CONCLUSIONS: The study findings support the potential association between RV infection and BA pathogenesis. However, the lack of an epidemiological reduction in BA following the introduction of the RV vaccine warrants caution in other studies. Further prospective multicenter studies are required to elucidate the causal role of RV infection in BA development.

Human herpesviruses (HHVs) cause central nervous system (CNS) infections; however, the role of neural autoantibodies remains unclear. We aimed to assess the presence of anti-N-methyl-D-aspartate receptor (anti-NMDAR) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in HHV-associated CNS infections. Seventeen adults with HHV DNA in the cerebrospinal fluid were tested using flow cytometry-based assays. None of the patients tested positive for anti-NMDAR antibodies. Anti-MOG antibodies were detected in two patients with VZV-associated CNS infection, one appearing after deterioration and the other at onset. Both patients recovered without sequelae. Anti-MOG antibodies may arise in VZV-associated CNS infections, warranting the consideration of autoimmune mechanisms.