Immunopathology of Fatal Human Variegated Squirrel Bornavirus 1 Encephalitis, Germany, 2011–2013

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.

First isolation, in-vivo and genomic characterization of zoonotic variegated squirrel Bornavirus 1 (VSBV-1) isolates

“…Nevertheless, they showed a moderate to severe non-purulent meningoencephalitis accompanied by activation of glia cells. These lesions resemble the inflammatory pattern in the CNS found in humans infected with VSBV-1 [ 1 , 3 , 4 ]. Detailing the CNS lesions in human VSBV-1-infection led to the assumption of an immune-mediated pathogenesis with comparable but also different features as known for BoDV-1 infections [ 4 ].…”

“…These lesions resemble the inflammatory pattern in the CNS found in humans infected with VSBV-1 [1,3,4]. Detailing the CNS lesions in human VSBV-1-infection led to the assumption of an immune-mediated pathogenesis with comparable but also different features as known for BoDV-1 infections [4]. Whether comparable immune mediated processes could be responsible for the inflammation in the CNS of VSBV-1 infected neonatal rats remains to be investigated, e.g.…”

“…Variegated squirrel bornavirus 1 (VSBV-1) is one of the most recently discovered zoonotic viruses associated with fatal encephalitis in human patients [1][2][3][4]. Variegated squirrels (Sciurus variegatoides), red-tailed squirrels (Sciurus granatensis), Finlayson's squirrels (Calloscirurus finlaysonii) and Swinhoei's striped squirrels (Tamiops swinhoei) were tested positive for this pathogen, in addition to Prevost squirrels (Callosciurus prevostii), which exhibit even higher total case numbers [5,6].…”

“…Variegated squirrels (Sciurus variegatoides), red-tailed squirrels (Sciurus granatensis), Finlayson's squirrels (Calloscirurus finlaysonii) and Swinhoei's striped squirrels (Tamiops swinhoei) were tested positive for this pathogen, in addition to Prevost squirrels (Callosciurus prevostii), which exhibit even higher total case numbers [5,6]. While the squirrels positively tested for VSBV-1 genome appeared to be in good health, humans infected with VSBV-1 developed a severe and fatal immune-pathogenic mediated encephalitis [1][2][3][4].…”

“…In vivo animal infection data, like e.g. an experimental evidence for the immune-mediated pathogenesis of VSBV-1-induced encephalitis as described in human VSBV-1 cases [ 4 ], were missing due to a lack of virus isolates and hitherto existing in vivo infection models.…”