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The Neuropathology of Fatal Encephalomyelitis in Human Borna Virus Infection

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The Neuropathology of Fatal Encephalomyelitis in Human Borna Virus Infection Acta Neuropathologica (2019) 138:653–665 https://doi.org/10.1007/s00401-019-02047-3 ORIGINAL PAPER The neuropathology of fatal encephalomyelitis in human Borna virus infection Friederike Liesche1 · Viktoria Ruf2 · Saida Zoubaa3 · Gwendolyn Kaletka1 · Marco Rosati4 · Dennis Rubbenstroth5 · Christiane Herden6 · Lutz Goehring7 · Silke Wunderlich8 · Miguel Frederic Wachter9 · Georg Rieder10 · Ines Lichtmannegger11 · Willibald Permanetter12 · Josef G. Heckmann13 · Klemens Angstwurm14 · Bernhard Neumann14 · Bruno Märkl15 · Stefan Haschka16 · Hans‑Helmut Niller17 · Barbara Schmidt17 · Jonathan Jantsch17 · Christoph Brochhausen18 · Kore Schlottau5 · Arnt Ebinger5 · Bernhard Hemmer8,19 · Markus J. Riemenschneider3 · Jochen Herms2,19 · Martin Beer5 · Kaspar Matiasek4 · Jürgen Schlegel1 Received: 4 June 2019 / Revised: 18 July 2019 / Accepted: 19 July 2019 / Published online: 26 July 2019 © The Author(s) 2019 Abstract After many years of controversy, there is now recent and solid evidence that classical Borna disease virus 1 (BoDV-1) can infect humans. On the basis of six brain autopsies, we provide the frst systematic overview on BoDV-1 tissue distribution and the lesion pattern in fatal BoDV-1-induced encephalitis. All brains revealed a non-purulent, lymphocytic sclerosing panencephalomyelitis with detection of BoDV-1-typical eosinophilic, spherical intranuclear Joest–Degen inclusion bodies. While the composition of histopathological changes was constant, the infammatory distribution pattern varied interindividu- ally, afecting predominantly the basal nuclei in two patients, hippocampus in one patient, whereas two patients showed a more difuse distribution. By immunohistochemistry and RNA in situ hybridization, BoDV-1 was detected in all examined brain tissue samples. Furthermore, infection of the peripheral nervous system was observed. This study aims at raising awareness to human bornavirus encephalitis as diferential diagnosis in lymphocytic sclerosing panencephalomyelitis. A higher attention to human BoDV-1 infection by health professionals may likely increase the detection of more cases and foster a clearer picture of the disease. Keywords Virus · Bornavirus · Borna disease virus (BoDV-1) · Zoonosis · Encephalitis Introduction organism via the olfactory network and spreads through the limbic system to nearly all cortical areas, brainstem, cer- The classical Borna disease virus 1 (BoDV-1; species Mam- ebellum, and spinal cord [9]. In contrast to dead-end hosts, malian 1 orthobornavirus) can lead to lethal infections in a reservoir hosts feature a disseminated virus distribution to broad range of mammals. The virus is endemically present nearly every organ with shedding of infectious virus [24]. in white-toothed bicolored shrews (Crocidura leucodon) [1, Other animals, including rats and bank voles, can be infected 7, 16], while horses and sheep are main accidental dead- experimentally via diferent routes [10, 19]. Until recently, end hosts [9]. Historically, a severe neurological disorder no report on confrmed human bornavirus infection existed. (Borna disease) due to an encephalomyelitis lymphocytaria In 2015, the frst human infections with another orthobor- non-purulenta with loss of neurons had been described for navirus (variegated squirrel 1 bornavirus [VSBV-1]; spe- accidental hosts [18]. It is assumed that the virus enters the cies Mammalian 2 orthobornavirus) were described, which resulted in lethal encephalitis of three breeders of variegated squirrels (Sciurus variegatoides). All three patients showed Friederike Liesche, Viktoria Ruf and Saida Zoubaa contributed similar central nervous system (CNS) symptoms with equally to the manuscript. lesions in cerebral cortex, basal nuclei, and brainstem, but without involvement of the spinal cord [17]. Subsequently, * Friederike Liesche [email protected] two more VSBV-1-induced human encephalitis cases occurred, whereof one was lethal [32, 33]. The frst evidence Extended author information available on the last page of the article Vol.:(0123456789)1 3 654 Acta Neuropathologica (2019) 138:653–665 for human infections with the “classical” BoDV-1 was pub- hematoxylin and eosin (H&E) stain, Grocott’s methena- lished by two simultaneous reports just recently in 2018. A mine silver stain, and periodic acid-Schif (PAS) stain. We group of three recipients of solid organ transplants from the conducted an established avidin–biotin complex technique same donor developed severe encephalitis of preliminary for immunohistochemistry (IHC) using the monoclonal unknown origin, which was later convincingly demonstrated Bo18 antibody, which is directed against the nucleoprotein to be BoDV-1-associated [28]. Furthermore, BoDV-1 infec- (N) of BoDV-1 [11], as described previously in animals tion led to the death of a previously healthy 25-year-old man [15, 35]. Furthermore, BoDV-1 RNA in situ hybridization [21]. Shortly afterwards, a report on a sporadic BoDV-1 (V-BoDV1-G targeting 2-969 of NC_001607-1:2236-3747, infection with initial symptoms mimicking a Guillain–Barré RNAscope®, Advanced Cell Diagnostics, Inc., USA) was syndrome was reported [5]. All fve patients sufered a mas- performed as described previously [34]. For patients 1, 2, 3, sive non-purulent encephalitis leading to death in four of the and 5, infltrating infammatory cells were characterized by cases [5, 21, 28]. One of the deceased immunocompromised IHC using antibodies directed against CD3 (Cell Marque, transplant recipients was autopsied and provided full insight The Netherlands; monoclonal, rabbit, dilution 1:500), CD20 into CNS and peripheral nerve pathology (patient 1). This (Dako Denmark A/S, Denmark; monoclonal, mouse, dilu- incident triggered a broad research on post mortem cases tion 1:500), CD4 (Ventana Roche, Switzerland; monoclonal, with yet non-classifed encephalitis. Our screening revealed rabbit, ready-to-use), CD8 (Ventana Roche, Switzerland; autoptic material of fve additional cases of fatal human monoclonal, rabbit, ready-to-use), CD68 (Dako Denmark BoDV-1. All patients had appeared completely healthy prior A/S, Denmark; monoclonal, mouse, dilution 1:15,000), to the neurologic disease. CD138 (Cell Marque, The Netherlands; monoclonal, mouse, With these six cases, our study provides the frst com- dilution 1:50), and Iba1 (abcam, USA; polyclonal, rabbit, prehensive description of the neuropathology of human dilution 1:500). These stainings were performed using BoDV-1 infection with focus on infammatory lesions and a fully-automated staining system (Ventana BenchMark virus distribution patterns at a systemic and cellular level. ULTRA; Ventana Medical Systems; Tucson; USA). Briefy, the slides were exposed to heat-induced epitope uncover- ing in pH 8.4 bufer at 95 °C for 40 min. After incubating Materials and methods with H2O2, the slides were incubated with the primary anti- bodies indicated above, followed by visualization using the This retrospective study was approved by the local ethi- 3,3′-diaminobenzidine-(DAB-)based OptiView DAB IHC cal committee of the Technical University Munich. The Detection Kit (Ventana Medical Systems). families of patients 1, 2, and 6 gave informed consent to To characterize the cellular distribution of the infection, complete autopsy, whereas the families of patients 3, 4, immunolabelling with Bo18 antibody was combined with and 5 agreed to brain autopsy only. For patients 1, 2, and cell markers Iba1 (abcam, USA; polyclonal rabbit, dilution 6, macroscopic evaluation of the thoracic and abdominal 1:500), GFAP (Dako Denmark A/S, Denmark; rabbit poly- cavity, including evaluation of all organs, was conducted clonal, dilution 1:500), S-100 (Dako Denmark A/S, Den- by two pathologists. For microscopic analysis, representa- mark; rabbit polyclonal, 1:500) and synaptophysin (Synaptic tive samples from peripheral organs, including heart, lung, Systems, Germany; rabbit polyclonal, dilution 1:200) using liver, kidney, trachea, esophagus, stomach, intestine, and an antibody removal agent (LinBlock, Linaris, Germany) others were obtained. Brain dissection was carried out by and a green second chromogen (Histogreen®, Linaris, two neuropathologists after routine formalin-fxation of the Germany). undissected brain. For microscopic analysis, representative In the same vein, RNA in situ hybridization of BoDV-1 samples from multiple selected regions of the brain and RNA (V-BoDV1-G targeting 2-969 of NC_001607-1:2236- spinal cord were retrieved from following areas: frontal, 3747, RNAscope®, Advanced Cell Diagnostics, Inc., USA) parietal and occipital cortex, hippocampus, basal ganglia, was performed, followed by immunohistochemical coun- mesencephalon, pons, medulla oblongata, cerebellum, as terstaining with glial fbrillary acidic protein (GFAP; Dako well as cervical, thoracic and lumbar parts of the spinal Denmark A/S, Denmark; monoclonal, mouse, dilution cord. From patients 1 and 6, peripheral nerves including 1:500), S-100 (Agilent, USA; polyclonal, rabbit, dilution the sciatic nerve and brachial plexus from patient 1, and 1:6000), myelin basic protein (MBP; Cell Marque Corpora- sural and femoral nerve as well as brachial and sacral plexus tion, USA; polyclonal, rabbit, ready-to-use, dilution 1:2), from patient 6 were sampled in addition to the autonomic neuroflament (NFpan; Dako Denmark A/S, Denmark; mon- nerve branches attached to visceral organs and tissues. All oclonal, mouse, dilution 1:200), Iba1 (abcam, USA; poly- tissue samples were further fxed in 10% bufered formalin clonal, rabbit,
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