Detection of Borna disease virus (BDV) antibodies and BDV RNA in psychiatric patients: evidence for high sequence conservation of human blood-derived BDV RNA

Abstract

In several vertebrate species, Borna disease virus (BDV), the prototype of a new group of animal viruses, causes central nervous system disease accompanied by diverse behavioral abnormalities. Seroepidemiological data indicate that BDV may contribute to the pathophysiology of certain human mental disorders. This hypothesis is further supported by the detection of both BDV antigens and BDV RNA in peripheral blood mononuclear cells (PBMCs) of patients with psychiatric disorders and the isolation of BDV from such PBMCs.Here we describe serological and molecular epidemiological studies on psychiatric patients and healthy individuals from the area of Homburg, Germany. Using a novel Western blot (immunoblot) assay, we found a BDV seroprevalence of 9.6% among 416 neuropsychiatric patients, which is significantly higher than the 1.4% found among 203 healthy control individuals. Human sera displayed a prominent immunoreactivity against the virus nucleoprotein, the p40 antigen. Reverse transcriptase-mediated PCR analysis of RNA extracted from PBMCs of a subset of 26 of the neuropsychiatric patients revealed that 50% were BDV RNA positive. Three of the 13 BDV RNA-positive patients also had BDV-positive serology, whereas one patient with serum antibodies to BDV p40 antigen did not harbor detectable BDV RNA in PBMCs. BDV p40 and p24 sequences derived from human PBMCs exhibited both a high degree of inter-and intrapatient conservation and a close genetic relationship to animal-derived BDV sequences.

Borna Disease Virus and the Brain

“…Sequence analysis revealed a high degree of conservation of both inter-and intrapatient BDV sequences, as well as a close genetic relationship between human and animal-derived BDV sequences [29,49,180]. This finding is consistent with the remarkable genetic stability of BDV in animals, which has been dealt with in a previous section.…”

“…This is remarkable for RNA virus isolates with different origin and passage history in animals and cultured cells. These sequences are also very similar to those obtained from field cases of BD in different animal species [21,184], as well as to sequences derived from human cases of BDV infection [29,49,108,180]. This extraordinary sequence conservation, uncommon for an animal NNS RNA virus, may indicate that there is a prevalent and stable species of BDV in nature, with the ability to infect several animal species, including humans.…”

“…Studies on Japanese healthy blood donors revealed a viral prevalence of 4.6% (8 of 172) [108] and 0% (0 of 36) [95]. Studies on German neuropsychiatric patients revealed a BDV RNA prevalence in PBMC of 50% (13 of 26), whereas 0% (0 of 23) of normal controls were positive for viral RNA [180]. These studies have also shown that patients harboring detectable levels of viral RNA in their PBMC are frequently BDV seronegative; conversely, BDV-seropositive individuals have frequently nondetectable levels of viral RNA [29,108,180].…”

“…Thus, the nuclear localization of BDV antigens in infected cells makes necessary the use of appropriate controls to discriminate between BDV-specific staining and nuclear staining due to autoantibodies. Increased specificity and sensitivity are now provided by Western blot assays that use either BDV-infected cell extracts [66,218], or recombinantly expressed BDV antigens [108,180]. Interestingly, results from studies conducted using this improved serologic test have still shown a significantly higher seroprevalence in neuropsychiatric patients (6.5-30%) compared to nonpsychiatric control groups (0 -1.4%) [66,108,180,218].…”

“…This might reflect strain differences due to geographical location. Nevertheless, this higher variability may have been overestimated by the experimental procedures used to determine these sequences (see discussion in [180]).…”