Development of a nonhuman primate model for mammalian bornavirus infection

Abstract

Until recently, it was assumed that members of the family Bornaviridae could not induce severe disease in humans. Today, however, Borna disease virus 1 (BoDV-1), as well as the more recently emerged variegated squirrel bornavirus 1 (VSBV-1), are known as causative agents of lethal encephalitis in humans. In order to establish animal models reflecting the pathogenesis in humans and for countermeasure efficacy testing, we infected twelve rhesus macaques (Macaca mulatta) either with VSBV-1 or with BoDV-1. For each virus, three monkeys each were inoculated with 2 × 104 focus forming units by the intracerebral route or by multiple peripheral routes (intranasal, conjunctival, intramuscular, and subcutaneous; same dose in total). All BoDV-1 and VSBV-1 intracerebrally infected monkeys developed severe neurological signs around 5 to 6 or 8 to 12 weeks postinfection, respectively. Focal myoclonus and tremors were the most prominent observations in BoDV-1 and VSBV-1-infected animals. VSBV-1-infected animals also showed behavioral changes. Only one BoDV-1 peripherally infected animal developed similar disease manifestations. All animals with severe clinical disease showed high viral loads in brain tissues and displayed perivascular mononuclear cuffs with a predominance of lymphocytes and similar meningeal inflammatory infiltrates. In summary, rhesus macaques intracerebrally infected with mammalian bornaviruses develop a human-like disease and may serve as surrogate models for human bornavirus infection.

Animal Model Alternatives in Filovirus and Bornavirus Research

“…Only recently were BoDV-1 and the newly discovered VSBV-1 shown to induce a meningoencephalitis and other neurological symptoms in rhesus macaques, closely resembling human disease [ 103 , 104 ]. Intracranially (i.c.…”

“…Intracranially (i.c. ), BoDV-1- or VSBV-1-infected animals initially displayed general symptoms of anorexia, sleepiness, and decreased activity, and they developed severe neurological signs, including focal myoclonus, tremors, and behavioral changes [ 103 ]. Interestingly, VSBV-1 neurological symptoms upon i.c.…”

“…Interestingly, VSBV-1 neurological symptoms upon i.c. inoculation were less severe, rather showing behavioral changes [ 103 ]. Similarly to human cases, lymphocytic perivascular cuffing and meningeal inflammatory infiltrates were detected in i.c.-infected NHPs.…”

“…Similarly to human cases, lymphocytic perivascular cuffing and meningeal inflammatory infiltrates were detected in i.c.-infected NHPs. Like in humans, VSBV-1-infected NHP post mortem analyses revealed a strict central neurotropism, while for BoDV-1 RNA also appeared in peripheral nervous tissue in few other organs [ 103 ].…”

“…In contrast, i.c. inoculation of rats with BoDV-1 causes non-fatal, acute meningoencephalitis and subsequent persistent infection associated with chronic debility and loss of brain tissue [ 105 , 106 , 107 , 108 , 109 ], prominently differing from the NHP model [ 103 ]. In Lewis rats, it is suggested that BoDV-1 meningoencephalitis and brain lesions are associated with immunopathological effects of the CD4+ and CD8+ T cell subsets [ 110 , 111 , 112 , 113 ].…”