Different susceptibility and pathogenesis of rabbit genotype 3 hepatitis E virus (HEV-3) and human HEV-3 (JRC-HE3) in SPF rabbits

Hepatitis E virus (HEV) is an increasingly important zoonotic infection in humans with HEV genotypes 3 and 4 being recognized as zoonotic pathogens. The relatively recently isolated genotype 3 rabbit HEV (rHEV-3) and the more well known genotype 3 isolates from humans and swine (hsHEV-3) have all been confirmed experimentally to be capable of infecting both non-human primates and specific-pathogen free (SPF) pigs. In a previous study rHEV-3 was shown to cause acute hepatitis in experimentally infected rabbits. However, whether hsHEV-3 can productively infect rabbits remained unclear. The objective of this study was to investigate the experimental infection of rabbits with human HEV-3 (hHEV-3, JRC-HE3), to compare it to that with rHEV-3 (CHN-BJ-rb14) and to further characterise the pathogenesis of the two isolates. All animals inoculated with rHEV-3 (CHN-BJ-rb14) became infected, exhibiting an intermittent viremia, elevated liver enzymes, and persistent fecal virus shedding throughout the 15 week study period. Liver histopathology showed acute inflammation and both positive- and negative-stranded viral RNA was detected in various tissues from necropsied rabbits. By contrast, neither sero-conversion nor alanine aminotransferase (ALT) elevation was observed in most rabbits inoculated with hHEV-3 (JRC-HE3). In addition, rHEV-3 (CHN-BJ-rb14) but not hHEV-3 (JRC-HE3) recovered from primary infected rabbits was transmissible to naive rabbits. These results showed that SPF rabbits are readily susceptible to infection with rHEV-3 (CHN-BJ-rb14) but not hHEV-3 (JRC-HE3), which might indicate the influence of viral genomic organization on its pathogenicity.