Hepatitis E Virus Strains in Rabbits and Evidence of a Closely Related Strain in Humans, France

Jacques Izopet

, Martine Dubois, Stéphane Bertagnoli, Sébastien Lhomme, Stéphane Marchandeau, Samuel Boucher, Nassim Kamar, Florence Abravanel, and Jean-Luc Guérin

Author affiliations: Institut National de la Santé et de la Recherche Médicale, Toulouse, France (J. Izopet, M. Dubois, S. Lhomme, N. Kamar, F. Abravanel); Faculté de Médecine Toulouse-Purpan, Université Toulouse III Paul-Sabatier, Toulouse (J. Izopet, S. Lhomme, N. Kamar, F. Abravanel); Le Centre Hospitalier Universitaire de Toulouse, Toulouse (J. Izopet, M. Dubois, S. Lhomme, N. Kamar, F. Abravanel); École Nationale Vétérinaire de Toulouse, Toulouse (S. Bertagnoli, J.-L. Guérin); Office National de la Chasse et de la Faune Sauvage, Nantes, France (S. Marchandeau); and Labovet, Les Herbiers, France (S. Boucher )

Abstract

Hepatitis E virus (HEV) strains from rabbits indicate that these mammals may be a reservoir for HEVs that cause infection in humans. To determine HEV prevalence in rabbits and the strains’ genetic characteristics, we tested bile, liver, and additional samples from farmed and wild rabbits in France. We detected HEV RNA in 7% (14/200) of bile samples from farmed rabbits (in 2009) and in 23% (47/205) of liver samples from wild rabbits (in 2007–2010). Full-length genomic sequences indicated that all rabbit strains belonged to the same clade (nucleotide sequences 72.2%–78.2% identical to HEV genotypes 1–4). Comparison with HEV sequences of human strains and reference sequences identified a human strain closely related to rabbit strain HEV. We found a 93-nt insertion in the X domain of open reading frame 1 of the human strain and all rabbit HEV strains. These findings indicate that the host range of HEV in Europe is expanding and that zoonotic transmission of HEV from rabbits is possible.

Hepatitis E virus (HEV) is a major cause of acute hepatitis in many developing countries in Asia and Africa, where it is transmitted by the fecal–oral route because of poor sanitation practices (1). Acute hepatitis E is also increasingly reported in industrialized countries, where the transmission is mainly zoonotic (2). The initial discovery of HEV transmission from domestic pigs (3) has been followed by evidence that other mammals, such as wild boars and deer, are also potential reservoirs of HEV (4). Although the course of HEV infection is generally self-limiting and asymptomatic (or symptomatic with acute hepatitis), fulminant hepatitis can occur in pregnant women and in persons with underlying liver disease (5–7). HEV infections can also become chronic in immunocompromised patients, such as recipients of solid-organ transplants (8–10), those with hematologic diseases (11,12), and patients infected with HIV (13–15).
HEV, genus Hepevirus, family Hepeviridae, is a positive-sense, single-stranded, nonenveloped RNA virus (16). The HEV genome is ≈7.2 kb long and contains 3 open reading frames (ORFs) as well as 5′ and 3′ untranslated regions: ORF1 encodes nonstructural proteins, ORF2 encodes the capsid protein, and ORF3 encodes a small phosphoprotein. Phylogenetic analysis of HEV sequences has led to the recognition of 4 major genotypes that infect mammals from a variety of species. HEV1 and HEV2 are restricted to humans and transmitted through contaminated water in developing countries. HEV3 and HEV4 infect humans, pigs, and other mammals and are responsible for sporadic cases of hepatitis E in developing and industrialized countries (2). HEV3 is distributed worldwide, whereas HEV4 largely is found in Asia. Although HEV3 and HEV4 infections have been linked to the consumption of raw or undercooked meats, such as pig liver sausages or game meats (17,18), the full spectrum of animals that are reservoirs of HEV is still unknown.
Recent studies have characterized new HEV genotypes in isolates from rats in Germany (19), wild boars in Japan (20), and farmed rabbits in the People’s Republic of China (21,22). Because the potential risk for zoonotic transmission of HEV from rabbits in France is unknown, and cases of autochthonous hepatitis E are commonly reported in this country (23,24), we investigated the prevalence of HEV in farmed and wild rabbits. We also looked for a genetic link between HEV strains circulating in rabbits and HEV strains circulating in humans in France.