Experimental Infection of Rabbits with Rabbit and Genotypes 1 and 4 Hepatitis E Viruses

Abstract

BackgroundA recent study provided evidence that farmed rabbits in China harbor a novel hepatitis E virus (HEV) genotype. Although the rabbit HEV isolate had 77–79% nucleotide identity to the mammalian HEV genotypes 1 to 4, their genomic organization is very similar. Since rabbits are used widely experimentally, including as models of infection, we investigated whether they constitute an appropriate animal model for human HEV infection.MethodsForty-two SPF rabbits were divided randomly into eleven groups and inoculated with six different isolates of rabbit HEV, two different doses of a second-passage rabbit HEV, and with genotype 1 and 4 HEV. Sera and feces were collected weekly after inoculation. HEV antigen, RNA, antibody and alanine aminotransferase in sera and HEV RNA in feces were detected. The liver samples were collected during necropsy subject to histopathological examination.FindingsRabbits inoculated with rabbit HEV became infected with HEV, with viremia, fecal virus shedding and high serum levels of viral antigens, and developed hepatitis, with elevation of the liver enzyme, ALT. The severity of disease corresponded to the infectious dose (genome equivalents), with the most severe hepatic disease caused by strain GDC54-18. However, only two of nine rabbits infected with HEV genotype 4, and none infected with genotype 1, developed hepatitis although six of nine rabbits inoculated with the genotype 1 HEV and in all rabbits inoculated with the genotype 4 HEV seroconverted to be positive for anti-HEV IgG antibody by 14 weeks post-inoculation.ConclusionsThese data indicate that rabbits are an appropriate model for rabbit HEV infection but are not likely to be useful for the study of human HEV. The rabbit HEV infection of rabbits may provide an appropriate parallel animal model to study HEV pathogenesis.

Zoonotic Hepatitis E Virus: Classification, Animal Reservoirs and Transmission Routes

“…Infection of SPF rabbits with rabbit HEV induces virus shedding in faeces, viremia and the development of hepatitis, characterised by histopathological changes and an increase in the level of ALT in the serum [95,96,97]. In addition, chronic hepatitis, characterised by liver inflammation and some degree of fibrosis, was observed in rabbits experimentally infected with rabbit HEV [95].…”

Host Immune Status and Response to Hepatitis E Virus Infection

“…Rabbits are susceptible to infection with at least some strains of HEV-3 and HEV-4 but appear to be resistant to infection with HEV-1 (211,212). Conversely, rabbit HEV strains can infect pigs and macaques (213,214), and they can replicate in two human cancer cell lines (96), suggesting the ability to adapt to other mammalian hosts.…”

Hepatitis E vaccine immunization for rabbits to prevent animal HEV infection and zoonotic transmission

“…Accumulative lines of evidence have indicated that rabbits are sensitive to HEV infection and seem to constitute an animal reservoir of HEV [34,39]. The fact that rabbits can be experimentally infected by sHEV-4 [40] or human HEV-4 [41] and that rHEV is transmissible from rabbits to cynomolgus macaques [42] both suggest that rabbits may be a new source of human HEV infection. Interestingly, a HEV strain in rabbits closely related to human HEV strain has been identified in France [36], and recently, a HEV strain closely related to a human HEV sequence was identified for the first time in the pet house rabbit [43].…”