This is the first study in Iranian people showing a fairly high prevalence of Bornavirus infection in healthy individuals including blood donors. The results meet reported data from Central Europe of about 30% based on the same infection marker (CIC). The study also supports previous findings that this neurotropic virus infection is more prevalent in psychiatric patients than in healthy donors. According to trends our results are supporting infection patterns in other countries, like Europe, the Americas and Asia which are based on specific antibody- and nucleic acid detection [9, 10, 15, 21, 35–42], despite of largely differing prevalence data. Based on measuring BDV released antigens or antigen-antibody complexes, like CICs [25, 27, 29, 30], our data showed a much better agreement.
Studies questioning and reporting the absence of BDV in both normal and psychiatrically diseased people remain inconclusive as long as no other cohorts have been investigated and no other methods have been applied. Among those are studies of Na et al.  and Hornig et al. .The latter group even neglected an own earlier positive study with contradictory results from the same country . On the other hand, the existence of a human BDV strain has recently been independently proven by an in vitro study in brain cells. Only the human virus was able to reduce proliferation and enhance apoptosis but not the animal-derived laboratory strain of BDV .
Our study used an established triple EIA which had been successfully applied to monitor point- and longitudinal prevalence of BDV infection markers in patients [25, 26]. In our hands, these EIAs were found to be easy to handle and to provide robust and reproducible measurements. It is unfortunate that general acceptance is still pending. In this study, consecutive sampling of admitted patients was not possible. Although the data only refer to cross-sectional sample analysis, BDV markers were significantly more prevalent in Iranian patients with mental diseases than in control subjects. These findings were similar to data reported from Germany [25, 26], Italy  Australia , the CSSR , China (Xia Liu, Peng Xie, pers. communication), and Lithuania (Violeta Mockeliūnienė, Robertas Bunevicius, pers. communication) where the same test system had been applied.
The presence of CIC with or without antibodies indicates a chronic infection; the presence of Ag, with or without CICs at the same time, a currently active infection. The finding of free anti-BDV antibody alone (no antigen, no CICs) is thought to indicate previous exposure to the agent, but not a current active infection . As shown in earlier reports CICs represent the major viral marker explaining the transient disappearance of antibodies and antigens in blood plasma between activated and dormant phases of virus infection, and by this providing also a clue for the true number of silently infected carriers in a healthy cohort or population [25, 26, 34].
Iranian psychiatric patients show a clearly elevated CIC sero-prevalence (40.4%) compared to healthy controls (27.5%). It is of special interest that 33.3% of samples from blood donations were silent virus carriers, a finding confirming Australian  and German pilot reports [17, 26], thus being quite in contrast to an earlier report . Transfusion issues relating to BDV infection are still awaiting further clarification .
BD, MDD and OCD patients presented with infection rates of 45.3%, 50.0% and 40.0%, respectively. However, significance levels were only reached in BD patients. This might be due to the small sample size, but in parametric data analysis, comparing OD values of absorbance (extinction), high levels of CICs in sera from BD and MDD patients were also significant.
In contrast to other reports [47, 48], we found a relatively high sero-prevalence of free Ab and Ag in schizophrenic patients (16.7% and 5.6%, respectively) which is consistent with a relatively low CIC sero-prevalence among those individuals (22.2%, see Table 2). In addition to schizophrenic patients, only BD patients showed free antibodies in their sera (7.8%). This implies that BDV antibodies are usually bound in immune complexes and are therefore becoming transiently absent in the blood stream.
It is of considerable interest that the CIC sero-prevalence adversely correlated with the corresponding age groups (linear regression done using age as continuous data, R = -0.116, p = 0.042), which means that the young patients had highest CIC values, although the age limit includes only adults 18 years and older. This leaves the question whether younger people are either more prone to BDV infection or their immune response is more prominent. It supports a recent finding that young children (from 4–6 months to 3 years of age) had even much higher infection rates, although this pilot study warrants further investigations [28, 34], In addition, it has to be further examined whether and to which extent vertical transmission of BDV in the pregnant horse , mouse  and human  contributes to higher infection rates at young age. In this regard, high prevalence of BDV in the normal population, lifelong persistence of the virus in infected subjects (patients or healthy people), and the so far undisclosed function of endogenized BDV genome stretches [2, 3, 16], might reflect further risk factors warranting urgent future investigations.
Interestingly, significant differences between female and male patients could be measured for the first time (Figure 2. middle, p = 0.031), showing a prevalence of CICs in 42.3% of females, and 38.7% in males. In favor of these findings, two female patients, belonging to the BD and MDD groups, had high CIC titers with levels above 0.6 (+++) (Table 5). The sero-prevalence among healthy controls, however, reached only 25.3% in females and 31.3% in males.
Such sex-related specific differences according to, titers and prevalence of an antibody response to foreign antigens, infectious agents, or even auto antigens are known from the literature [51–55]. Females usually exhibit a stronger humoral immune response, as especially known after vaccination and infection with microbial agents. In fact, estrogens exert stimulatory effects on B cell proliferation and serum IgG levels, whereas testosterone may suppress B cell function [56, 57].
In conclusion, Iranian people seem to fit into the pattern of BDV infections, so far reported worldwide . Moreover, the study benefits from using prevalent infection markers and a highly specific and effective test system [26, 34]. The study confirms evidence for a high infection prevalence, similar to Central Europe, in one third of healthy Iranian subjects, contrasting elevated levels in patients with mood disorders. In view of millions of people worldwide suffering from depression and the huge related health care costs , this study points again to integrating BDV infection surveillance in psychiatric research  rather than to continue in underplaying its impact.