Antagonistic activity against innate immunity determines virulence in mammalian bornaviruses

Mammalian Bornaviruses include the classic Borna disease virus isolated from schizophrenic patients (BoDV-1) and the emerging and highly fatal zoonotic Variegated squirrel bornavirus (VSBV-1). The two share similar cell tropisms and core viral ribonucleic compatibility but the cause and underlying reason for the  VSBV-1 higher virulence have remained unclear.By use of Minigenome and functional assays, VSBV-1 phosphoprotein (P) was shown to boost BoDV-1 polymerase activity but lacked the innate immune-suppressive capabilities of BODV-1 P. BoDV-1 P requires X co-expression to transport to the cytoplasm but VSBV-1 P mostly localizes to the cytoplasm independently. This is driven by specific amino acid differences in its N-terminal nuclear localization signal. In the investigation of invivo pathogenesis, a recombinant chimeric virus (rBoDV-1 XPV) which carried the VSBV-1 X/P genes was engineered. rBoDV-1 XPV showed replication kinetics in vitro similar to wild-type BoDV-1 (Wt), but it caused 100% mortality in adult rats following intranasal infection. Histopathological analysis showed that rBoDV-1 XPV caused severe neuroinflammatory response with microgliosis, perivascular cuffing, high viral titers, and marked upregulation of pro-inflammatory cytokines in rat brains. VSBV-1 virulence is driven by weak innate immune antagonisms and cytoplasmic viral replication that causes severe and lethal immunopathology.
(MCW)