Human Borna disease virus 1 encephalitis shows marked pro-inflammatory biomarker and tissue immunoactivation during the course of disease

Rauch, Jessica; Steffen, Johanna Friederike; Muntau, Birgit; Gisbrecht, Jana; Pörtner, Kirsten; Herden, Christiane; Niller, Hans Helmut; Bauswein, Markus; Rubbenstroth, Dennis; Mehlhoop, Ute; Allartz, Petra; Tappe, Dennis

doi:10.1080/22221751.2022.2098831

Cited by 14 publications

(16 citation statements)

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“…BoDV-1 replicates within the cell nucleus and leads to persistent infections [ 8 ]. In spill-over hosts, severe clinical symptoms are attributed to an immunopathology, driven by a dysregulated inflammation and a presumably T-cell-mediated tissue destruction [ 13 , 14 , 15 ]. After initial unspecific symptoms, the clinical course of the disease is characterized by a rapid onset of severe neurological symptoms including memory loss, seizures, apnea, and deep coma.…”

Section: Introductionmentioning

confidence: 99%

Human Infections with Borna Disease Virus 1 (BoDV-1) Primarily Lead to Severe Encephalitis: Further Evidence from the Seroepidemiological BoSOT Study in an Endemic Region in Southern Germany

Bauswein

Eidenschink

Knoll

et al. 2023

Viruses

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More than 40 human cases of severe encephalitis caused by Borna disease virus 1 (BoDV-1) have been reported to German health authorities. In an endemic region in southern Germany, we conducted the seroepidemiological BoSOT study (“BoDV-1 after solid-organ transplantation”) to assess whether there are undetected oligo- or asymptomatic courses of infection. A total of 216 healthy blood donors and 280 outpatients after solid organ transplantation were screened by a recombinant BoDV-1 ELISA followed by an indirect immunofluorescence assay (iIFA) as confirmatory test. For comparison, 288 serum and 258 cerebrospinal fluid (CSF) samples with a request for tick-borne encephalitis (TBE) diagnostics were analyzed for BoDV-1 infections. ELISA screening reactivity rates ranged from 3.5% to 18.6% depending on the cohort and the used ELISA antigen, but only one sample of a patient from the cohort with requested TBE diagnostics was confirmed to be positive for anti-BoDV-1-IgG by iIFA. In addition, the corresponding CSF sample of this patient with a three-week history of severe neurological disease tested positive for BoDV-1 RNA. Due to the iIFA results, all other results were interpreted as false-reactive in the ELISA screening. By linear serological epitope mapping, cross-reactions with human and bacterial proteins were identified as possible underlying mechanism for the false-reactive ELISA screening results. In conclusion, no oligo- or asymptomatic infections were detected in the studied cohorts. Serological tests based on a single recombinant BoDV-1 antigen should be interpreted with caution, and an iIFA should always be performed in addition.

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Section: Introductionmentioning

confidence: 99%

Human Infections with Borna Disease Virus 1 (BoDV-1) Primarily Lead to Severe Encephalitis: Further Evidence from the Seroepidemiological BoSOT Study in an Endemic Region in Southern Germany

Bauswein

Eidenschink

Knoll

et al. 2023

Viruses

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“…IgG seroconversion occurs late during the course of the disease when severe neurological symptoms are already present [ 7 ]. Given the T-cell pathology of Borna disease and the previously described elevation of IFN-γ in the serum and CSF of patients with this infection [ 14 ], we addressed the question of whether an IFN-γ-based ELISpot is suitable in diagnosing patients with BoDV-1 infections. As we previously measured the serological responses against BoDV-1 N, X, and P protein by an ELISA system, we utilized 15-mer peptides covering these proteins for the stimulation of isolated PBMC.…”

Section: Discussionmentioning

confidence: 99%

“…T cells are present in virus-infected brain regions of BoDV-1 patients, with CD4 positive cells outnumbering CD8 positive cells [ 12 ]. In addition, an elevation of pro-inflammatory markers such as IFN-γ, IL-6, and chemokines (CCL-2, CCL-5, CXCL-10, IL-8) has been described in the serum and CSF of patients suffering from BoDV-1 infection [ 14 ]. As for tuberculosis and cytomegalovirus infections, the detection of pathogen-specific T cells is already exploited for diagnostic tests [ 15 ], we addressed the question of whether BoDV-1 infections can be diagnosed using a modified IFN-γ-based ELISpot with overlapping peptide pools of three BoDV-1-specific proteins.…”

Section: Introductionmentioning

confidence: 99%

IFN-γ-Based ELISpot as a New Tool to Detect Human Infections with Borna Disease Virus 1 (BoDV-1): A Pilot Study

Eidenschink

Knoll

Tappe

et al. 2023

Viruses

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More than 40 human infections with the zoonotic Borna disease virus 1 (BoDV-1) have been reported to German health authorities from endemic regions in southern and eastern Germany. Diagnosis of a confirmed case is based on the detection of BoDV-1 RNA or BoDV-1 antigen. In parallel, serological assays such as ELISA, immunoblots, and indirect immunofluorescence are in use to detect the seroconversion of Borna virus-reactive IgG in serum or cerebrospinal fluid (CSF). As immunopathogenesis in BoDV-1 encephalitis appears to be driven by T cells, we addressed the question of whether an IFN-γ-based ELISpot may further corroborate the diagnosis. For three of seven BoDV-1-infected patients, peripheral blood mononuclear cells (PBMC) with sufficient quantity and viability were retrieved. For all three patients, counts in the range from 12 to 20 spot forming units (SFU) per 250,000 cells were detected upon the stimulation of PBMC with a peptide pool covering the nucleocapsid protein of BoDV-1. Additionally, individual patients had elevated SFU upon stimulation with a peptide pool covering X or phosphoprotein. Healthy blood donors (n = 30) and transplant recipients (n = 27) were used as a control and validation cohort, respectively. In this pilot study, the BoDV-1 ELISpot detected cellular immune responses in human patients with BoDV-1 infection. Its role as a helpful diagnostic tool needs further investigation in patients with BoDV-1 encephalitis.

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“…The main hypothesis is that infections occur via uptake of contaminated viruscontaining particles via the olfactory route [11]. Studies indicate that the virus replicates rst in neurons and then in astrocytes, but not microglia [14]. The virus induces an increasing pro-in ammatory immune activation during BoDV-1 encephalitis [14], either as part of the host´s normal immune reaction or as a dysbalanced pro-in ammatory state, with lymphocytic-mediated (preferably CD8+) degeneration of the brain [15].…”

Section: Discussionmentioning

confidence: 99%

“…Studies indicate that the virus replicates rst in neurons and then in astrocytes, but not microglia [14]. The virus induces an increasing pro-in ammatory immune activation during BoDV-1 encephalitis [14], either as part of the host´s normal immune reaction or as a dysbalanced pro-in ammatory state, with lymphocytic-mediated (preferably CD8+) degeneration of the brain [15]. Previous single reports on a theoretical BoDV-1 involvement for psychiatric symptoms in non-symptomatic carriers [16,17] should be interpreted very cautiously, as they were not independently validated, failed in interlaboratory comparisons or could be the result of result of a laboratory contamination [13,18].…”

Section: Discussionmentioning

confidence: 99%

A potential role for early hyponatremia in the diagnosis of Borna-virus encephalitis?

Lourbopoulos

Schnurbus

Guenther

et al. 2023

Preprint

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Background The first case of fatal Borna Virus-1 encephalitis (BoDV-1) was reported in 2018. Here, we report another fatal case of BoDV-1 encephalitis with early severe hyponatremia, indicative of neurohypophysial dysfunction. Case presentation: A 77-year-old female living in southern Germany was admitted to hospital in 2020 due to rapidly progressing word-finding difficulties, personality changes, global disorientation, diffuse cognitive slowness, and gait ataxia, initially without fever. After a rapid deterioration with fever, gait instability and ataxia, rapid cognitive decline, meningism, epileptic seizures, aphasia, and signs of latent right hemiparesis, the suspicion of a (meningo-)encephalitis was set. Furthermore, an unexplained, severe hyponatremia had been present since admission. Laboratory workup in cerebrovascular fluid (CSF) and serum as well as brain imaging was negative. Despite extensive empirical antiviral, antimicrobial, and immunosuppressive treatment efforts, the patient fell into coma (day 5), lost all brainstem functions (day 18), and remained fully dependent on invasive mechanical ventilation. Finally, she clinically developed a status of brain death and died 42 days after initial admission. Brain autopsy confirmed an extensive, diffuse, and severe affection of neocortical, subcortical and cerebellar structures as well as the neurohypophysis due to infection with BoDV-1. In light of the autopsy results, the hyponatremia could imply an early basal brain involvement, which could narrow down the initial differential diagnosis. Conclusion The diagnosis of BoDV-1 encephalitis remains clinically challenging. The disease progresses quickly to irreversible brain damage. An early, unexplained, hyponatremia in the presence of severe and rapidly evolving encephalitis may narrow down the diagnosis.

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Human Borna disease virus 1 encephalitis shows marked pro-inflammatory biomarker and tissue immunoactivation during the course of disease

Cited by 14 publications

References 58 publications

Human Infections with Borna Disease Virus 1 (BoDV-1) Primarily Lead to Severe Encephalitis: Further Evidence from the Seroepidemiological BoSOT Study in an Endemic Region in Southern Germany

Human Infections with Borna Disease Virus 1 (BoDV-1) Primarily Lead to Severe Encephalitis: Further Evidence from the Seroepidemiological BoSOT Study in an Endemic Region in Southern Germany

IFN-γ-Based ELISpot as a New Tool to Detect Human Infections with Borna Disease Virus 1 (BoDV-1): A Pilot Study

A potential role for early hyponatremia in the diagnosis of Borna-virus encephalitis?

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