CIENCIASMEDICASNEWS: Ahead of Print - Immunopathology of Fatal Human Variegated Squirrel Bornavirus 1 Encephalitis, Germany, 2011–2013 - Volume 25, Number 6—June 2019 - Emerging Infectious Diseases journal

Author affiliations: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany (D. Tappe, J. Schmidt-Chanasit, J. Rauch, P. Allartz); German Centre for Infection Research, Hamburg (J. Schmidt-Chanasit); University of Giessen, Giessen, Germany (C. Herden)

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.

Variegated squirrel bornavirus (VSBV-1; family Bornaviridae, species Mammalian 2 orthobornavirus) is a new zoonotic virus that causes severe and eventually fatal encephalitis in humans. VSBV-1 was discovered retrospectively in 2015 in a cluster of 3 fatal encephalitis cases among private breeders of exotic variegated squirrels (Sciurus variegatoides) in eastern Germany (1). Phylogeny analyses showed that this virus forms a separate lineage within the Bornaviridae family. VSBV-1 is related to, but distinct from, the classical Borna disease virus 1 (BoDV-1; species Mammalian 1 orthobornavirus). Recently, also in retrospect, VSBV-1 was shown to be responsible for fatal limbic encephalitis in a zoo animal caretaker after contact with an exotic Prevost’s squirrel (Callosciurus prevostii) in northern Germany (2). The virus is of unknown origin (3) and most likely transmitted by bites and scratches of infected exotic squirrel species of the subfamilies Sciurinaefrom Central America and Callosciurinae from Southeast Asia (1,2) in holdings in Europe. The animals are asymptomatic and show high viral RNA loads, not only in the brain but also in organs capable of secretion and excretion, such as the kidney, urinary bladder, skin, and oropharynx (1,3,4). The distribution of viral RNA and antigen in the human brain has been described only in 1 patient (the patient with limbic encephalitis) (2). The pathophysiology of human VSBV-1 infection and the immune response toward the virus in humans is unknown.

We here summarize clinical data of all 4 known human VSBV-1 encephalitis cases and describe the distribution of VSBV-1 in different brain areas as determined by real-time reverse transcription PCR (RT-PCR) and immunohistochemical (IHC) analysis in the initial encephalitis cluster. 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.