Lethal Borna disease virus 1 (BoDV-1) infections of humans and animals – in-depth molecular epidemiology and phylogeography

Abstract

Borna disease virus 1 (BoDV-1) is the causative agent of Borna disease, a progressive and mostly fatal neurologic disorder of domestic mammals and humans, resulting from spill-over infection from its natural reservoir host, the bicolored white-toothed shrew (Crocidura leucodon). The known BoDV-1 endemic area is remarkably restricted to parts of Germany, Austria, Switzerland and the Principality of Liechtenstein. To gain comprehensive data on the occurrence of BoDV-1, we analysed diagnostic material from suspected fatal BoDV-1-induced encephalitis cases in domestic mammals and humans. BoDV-1 infection was confirmed by RT-qPCR in 207 of 231 domestic mammals (89.6%), 28 of 29 humans (96.6%) and seven shrews, mainly within the known endemic area. By reporting multiple unpublished cases, this study raises the number of published laboratory-confirmed human BoDV-1 infections to 46 and provides a first comprehensive summary. Generation of 136 new complete or partial BoDV 1 genome sequences from animals and humans facilitated an in-depth phylogeographic analysis. Consistent with the low mobility of its reservoir host, BoDV-1 sequences showed a remarkable geographic association, with individual phylogenetic clades occupying distinct and barely overlapping dispersal areas. The closest genetic relatives of most human-derived BoDV-1 sequences were located at distances of less than 40 km from the patient’s residence, indicating that spill-over transmission from the natural reservoir usually occurs in the region of the patient´s residence. In summary, the novel and extended phylogeographic data allow for the definition of risk areas for zoonotic BoDV-1 transmission and facilitate the assessment of geographical sources for individual infection events.