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Are human Borna disease virus 1 infections zoonotic and fatal? – Authors' reply

2020; Elsevier BV; Volume: 20; Issue: 6 Linguagem: Inglês

10.1016/s1473-3099(20)30379-0

1474-4457

Dennis Rubbenstroth, Hans Helmut Niller, Klemens Angstwurm, Martin Schwemmle, Martin Beer,

Viral Infections and Immunology Research

Liv Bode and colleagues bemoan our omission of widespread, endemic Borna disease virus 1 (BoDV-1) infections in humans in our study.1Niller HH Angstwurm K Rubbenstroth D et al.Zoonotic spillover infections with Borna disease virus 1 leading to fatal human encephalitis, 1999–2019: an epidemiological investigation.Lancet Infect Dis. 2020; 20: 467-477Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar However, the evidence of this postulated global prevalence remains insufficient. Our Article substantiates the ample evidence that BoDV-1 can cause fatal encephalitis in humans and other mammals within confined geographical regions. These cases were unequivocally confirmed by a number of standard methods (PCR, serology, virus isolation, immunohistochemistry, whole-genome sequencing) done in multiple independent laboratories.2Rubbenstroth D Schlottau K Schwemmle M Rissland J Beer M Human bornavirus research: Back on track!.PLoS Pathog. 2019; 15e1007873Crossref PubMed Scopus (20) Google Scholar Phylogenetic analysis has consistently shown stable genetic clusters correlating with geographic origin but not with host species. This pattern strongly points towards spill-over infections into humans from a regionally bound reservoir as opposed to human transmission. Indeed, bicoloured white-toothed shrews have been repeatedly reported as reservoirs.2Rubbenstroth D Schlottau K Schwemmle M Rissland J Beer M Human bornavirus research: Back on track!.PLoS Pathog. 2019; 15e1007873Crossref PubMed Scopus (20) Google Scholar By contrast, Bode and colleagues postulate that human BoDV-1 infection primarily manifests as non-fatal, chronic infections that are endemic to humans globally (up to 30% prevalence) and are associated with various psychiatric disorders. The claims are purportedly shown with non-standard diagnostic assays, primarily through detection of viral RNA by nested PCR and detection of circulating immune complexes in human blood.2Rubbenstroth D Schlottau K Schwemmle M Rissland J Beer M Human bornavirus research: Back on track!.PLoS Pathog. 2019; 15e1007873Crossref PubMed Scopus (20) Google Scholar However, over a period of more than 20 years, the existence of BoDV-1 circulating immune complexes and the validity of the respective assays have yet to be confirmed independently. Attempts by others to reproduce these findings have been plagued with difficulty.3Wolff T Heins G Pauli G Burger R Kurth R Failure to detect Borna disease virus antigen and RNA in human blood.J Clin Virol. 2006; 36: 309-311Crossref PubMed Scopus (33) Google Scholar Moreover, multiple attempts to identify endemic BoDV-1 in psychiatric patients and healthy controls by RNA detection in blood samples have either failed, or positive findings were later identified as laboratory contamination.2Rubbenstroth D Schlottau K Schwemmle M Rissland J Beer M Human bornavirus research: Back on track!.PLoS Pathog. 2019; 15e1007873Crossref PubMed Scopus (20) Google Scholar, 4Dürrwald R Kolodziejek J Herzog S Nowotny N Meta-analysis of putative human bornavirus sequences fails to provide evidence implicating Borna disease virus in mental illness.Rev Med Virol. 2007; 17: 181-203Crossref PubMed Scopus (57) Google Scholar, 5Hornig M Briese T Licinio J et al.Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder.Mol Psychiatry. 2012; 17: 486-493Crossref PubMed Scopus (67) Google Scholar Thus, arguments about the phenotypic particularities of a single putative human BoDV-1 isolate or reference to a clinical trial whose last patient was evaluated in 2002 are irrelevant until such isolates and patients are unequivocally verified as authentic human BoDV-1 infections. The well known, virus-independent effects of amantadine on Parkinson's disease and other neurological conditions further undermine the hypothesis that it might improve depression through an antiviral mechanism.6Huber TJ Dietrich DE Emrich HM Possible use of amantadine in depression.Pharmacopsychiatry. 1999; 32: 47-55Crossref PubMed Scopus (98) Google Scholar Our report intended to illustrate the human health risk posed by BoDV-1 due to zoonotic spillover based on the best evidence available. Although it is difficult to formally exclude the possibility of endemic infection by a non-cytolytic, neurotropic virus, we did not consider this topic to merit special consideration given the absence of any robust and reproducible evidence of widespread human BoDV-1 infection. We declare no competing interests. Zoonotic spillover infections with Borna disease virus 1 leading to fatal human encephalitis, 1999–2019: an epidemiological investigationBoDV-1 infection has to be considered as a potentially lethal zoonosis in endemic regions with reported spillover infections in horses and sheep. BoDV-1 infection can result in fatal encephalitis in immunocompromised and apparently healthy people. Consequently, all severe encephalitis cases of unclear cause should be tested for bornaviruses especially in endemic regions. Full-Text PDF Are human Borna disease virus 1 infections zoonotic and fatal?Hans H Niller and colleagues1 investigated eight new retrospective cases of human fatalities (1999–2019) in Germany caused by Borna disease virus 1 (BoDV-1). From autopsy brain samples, they were even able to retrieve an isolate (patient P8). This comprehensive report and other fatal encephalitis cases in transplant recipients have increased public awareness of the potential of classical BoDV as a human pathogen. Niller and colleagues1 used phylogenetic analyses (partial nucleoprotein gene sequences; 1056 nucleotides) to advocate the theory that human BoDV-1 infection is a very rare, potentially lethal zoonosis transmitted by bicoloured white-toothed shrews, which occur in narrow endemic clusters of southern Germany. Full-Text PDF