Abstract
Variegated squirrel bornavirus 1 (VSBV-1) is a zoonotic virus that causes fatal encephalitis in humans who are infected after contact with exotic squirrels. We analyzed the brain lesions and the immune responses in all 4 known human cases that showed panencephalitis. Inflammatory infiltrates in areas positive for VSBV-1 RNA and antigen consisted of CD4+ and CD8+ T cells, with perivascular B-cell accumulation. Strong microglial response and bizarre astroglial expansion were present. Areas of malacia contained neutrophils and foamy microglia and macrophages. Immunopathologic examination during infection showed cleavage of caspase 3 in brain cells adjacent to CD8+ cells and widespread p53 expression, hallmarks of apoptosis. Cerebrospinal fluid analyses over time demonstrated increasing protein concentrations and cell counts, paralleled by pathologic lactate elevations in all patients. The most severe cerebrospinal fluid and histologic changes occurred in the patient with the highest viral load, shortest duration of disease, and most medical preconditions.
Highlights
Variegated squirrel bornavirus 1 (VSBV-1) is a zoonotic virus that causes fatal encephalitis in humans who are infected after contact with exotic squirrels
We focus on the characterization of the central nervous system (CNS) immunologic response to VSBV-1 by IHC analyses of immune cells in the brain of all patients, as well as by examination of cerebrospinal fluid (CSF) reactions over time during the disease
We focused on the local immune response in brain tissue, as well as CSF reactions during infection
Summary
For patient 4, real-time RT-PCR analyses for VSBV-1 RNA in different brain areas and internal organs had been performed previously [2]. Medac-diagnostika.de) at 95°C for CD177, EDTA (pH 8 for CD4 and p53), or citrate (pH 6 for CD3, CD20, CD8, CD68, HLA-DR, iNOS, TUNEL, and Ki67) and endogenous peroxidase blocking, the FFPE tissue sections were incubated with the respective antibodies in Antibody Diluent Solution (Zytomed) at 4°C overnight. This step was followed by incubation with the DCS-AEC 2 Component Detection Kit and 3-amino-9-ethylcarbazole substrate (DCS, http://www.dcs-diagnostics.de) for immunoperoxidase staining or the DCS AP Detection Kit and Fast Blue substrate (DCS) for immunophosphatase staining. Intrathecal antibody synthesis was demonstrated by testing for oligoclonal bands (isoelectric focusing and immunofixation of IgG parallel in serum and CSF) and by calculation of the IgM, IgA, and IgG index (ratio between CSF and serum immunoglobulin class after correcting for albumin concentrations in the CSF and serum)
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