Hepeviridae: An expanding family of vertebrate viruses

Infection, Genetics and Evolution 27 (2014) 212–229

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Review

Hepeviridae: An expanding family of vertebrate viruses Reimar Johne a, Paul Dremsek b, Jochen Reetz a, Gerald Heckel c,d, Michael Hess e, Rainer G. Ulrich b,⇑ a

Federal Institute for Risk Assessment, Berlin, Germany Friedrich-Loeffler-Institut, Institute for Novel and Emerging Infectious Diseases, Greifswald-Insel Riems, Germany c University of Bern, Institute of Ecology and Evolution, Bern, Switzerland d Swiss Institute of Bioinformatics, Genopode, Lausanne, Switzerland e Clinic for Poultry and Fish Medicine, Department for Farm Animals and Veterinary Public Health, University of Veterinary Medicine (Vetmeduni Vienna), Vienna, Austria b

a r t i c l e

i n f o

Article history: Received 6 March 2014 Received in revised form 25 June 2014 Accepted 26 June 2014 Available online 19 July 2014 Keywords: Hepeviridae Hepatitis E virus Genome organisation Reservoir Cross-species transmission

a b s t r a c t The hepatitis E virus (HEV) was first identified in 1990, although hepatitis E-like diseases in humans have been recorded for a long time dating back to the 18th century. The HEV genotypes 1–4 have been subsequently detected in human hepatitis E cases with different geographical distribution and different modes of transmission. Genotypes 3 and 4 have been identified in parallel in pigs, wild boars and other animal species and their zoonotic potential has been confirmed. Until 2010, these genotypes along with avian HEV strains infecting chicken were the only known representatives of the family Hepeviridae. Thereafter, additional HEV-related viruses have been detected in wild boars, distinct HEV-like viruses were identified in rats, rabbit, ferret, mink, fox, bats and moose, and a distantly related agent was described from closely related salmonid fish. This review summarizes the characteristics of the so far known HEV-like viruses, their phylogenetic relationship, host association and proposed involvement in diseases. Based on the reviewed knowledge, a suggestion for a new taxonomic grouping scheme of the viruses within the family Hepeviridae is presented. Ó 2014 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Virus structure and genome organisation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Host association and virus transmission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mammalian HEV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Human genotypes 1 and 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Human zoonotic genotypes 3 and 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Rabbit HEV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Novel genotypes in wild boar. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Novel HEV-related virus in moose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Rat HEV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7. Carnivore HEV: strains detected in ferret, fox and mink . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8. Bat HEV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Avian HEV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Fish hepevirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Taxonomic considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

212 213 213 214 214 217 220 220 220 220 221 221 222 222 223 224 225 225 225

⇑ Corresponding author. Address: Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Institute for Novel and Emerging Infectious Diseases, Südufer 10, D-17493 Greifswald-Insel Riems, Germany. Tel.: +49 3835171159; fax: +49 3835171192. E-mail address: rainer.ulrich@fli.bund.de (R.G. Ulrich). http://dx.doi.org/10.1016/j.meegid.2014.06.024 1567-1348/Ó 2014 Elsevier B.V. All rights reserved.

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1. Introduction In the 1950s, large outbreaks of jaundice were reported in India. The obviously novel disease was described as enterically transmitted non A-, non B-hepatitis (Wong et al., 1980). However, a recent re-review of monographs published in the 19th century identified several descriptions on hepatitis E-like outbreaks already in the last decade of the 18th century, mainly in Western Europe and several of its colonies (Teo, 2012). One of the first described putative hepatitis E outbreaks occurred in 1794 in Lüdenscheid in the Palatinate, Germany (Teo, 2012). However, a detailed description of the course of this type of hepatitis was not available until 1983 (Balayan et al., 1983). This was achieved by an experimental infection of a human volunteer with non A-, non B-hepatitis agent via the faecal-oral route. Furthermore, viral particles could be detected in the volunteer’s stool by immune electron microscopy (Balayan et al., 1983). In 1991, the etiological agent of the disease was defined as hepatitis E virus (HEV), a name adopted later by other authors (Reyes et al., 1990). The sequencing of the entire HEV genome led to the first identification of immunogenic epitopes (Tam et al., 1991; Yarbough et al., 1991). This enabled the development of serological assays able to detect antibodies against HEV (Dawson et al., 1992). Before the introduction of specific serological tests, the diagnosis of hepatitis E was based solely on the exclusion of serological markers of hepatitis A and B virus infections in combination with the monitoring of epidemiological characteristics. In 1999, an HEV-related agent was further characterized, which appeared already in the 1980s in chickens in Australia (Payne et al., 1999). In 1997 and 1999, HEV was reported in domestic pigs and wild boars in the USA and Australia, respectively (Meng et al., 1997; Chandler et al., 1999). Until then, transmission of HEV was believed to occur by the human-to-human route only and mainly by water resources contaminated with human faeces. Especially the detection of similar HEV strains in pigs and humans now lead to the assumption of an additional zoonotic transmission route for this virus. In the following years, accumulating evidence suggested that mainly sporadic hepatitis E cases in industrialized countries are caused by zoonotic transmission of HEV, with pigs, wild boars, deer and other mammals representing possible reservoirs for the virus (Meng et al., 1998b; Meng, 2010). Since 2010, when a novel HEV-related virus was identified in Norway rats using newly developed broadly reacting detection methods of the HEV genome (Johne et al., 2010a), an increasing number of distinct HEV-like viruses were found in other rat species, rabbit, ferret, mink, fox, several bat species and moose, and a distantly related agent was described from related salmonid fish species. However, their zoonotic potential has not been clarified so far and their effect on human hepatitis E epidemiology is largely unknown. This review summarizes the characteristics of the so far known HEV-like viruses, their phylogenetic relationship, host association, zoonotic potential and involvement in disease in humans and reservoir animals. Based on the findings, a suggestion for a new taxonomic grouping scheme of the viruses within the family Hepeviridae has been developed. 2. Virus structure and genome organisation Hepatitis E virions are non-enveloped and icosahedral with a diameter of approx. 28–35 nm as shown exemplarily in Fig. 1. The virus consists of 180 capsomers formed by the open reading frame (ORF) 2-encoded capsid protein and contains the viral genome (Xing et al., 1999). However, recent density gradient analyses of HEV derived from tissue culture and serum of patients indicated the presence of a fraction of HEV, which harbour lipid-associated membranes as well as the virus protein encoded by ORF3 (Okamoto, 2013). A similar membrane hijacking has been reported

Fig. 1. Transmission electron micrograph of hepatitis E virions. The genotype 3 strain 47832c (Johne et al., 2014) was propagated in the human lung carcinoma cell line A549 persistently infected with the strain. Cell culture supernatant was collected at 14 days after seeding of the cells. The virus was purified by caesium chloride density gradient ultracentrifugation and negative contrasted using uranyl acetate. The bar corresponds to 100 nm.

for hepatitis A virus, a picornavirus, with broad implications for viral egress mechanisms and host immune responses (Feng et al., 2013). The hepevirus genome is a single stranded RNA of positive polarity with a length of approx. 7 kb (Meng et al., 2012). It is capped at the 50 -end and contains a 30 -polyadenylation (Tam et al., 1991). The genome generally contains three ORFs, which are flanked by short 50 - and 30 -untranslated regions (UTR). ORF1 is located at the 50 -end and encodes a polyprotein of approx. 1700 amino acid residues, which is processed by a hitherto unknown protease into non-structural proteins (Panda et al., 2000; Paliwal et al., 2014). The ORF1-derived polyprotein contains parts with sequence similarities to methyltransferases, papain-like proteases, helicases and RNA-dependent RNA polymerases, as well as a hypervariable region. ORF2 is located at the 30 -end of the genome and encodes the capsid protein with a length of approx. 660 amino acid residues. ORF3 overlaps with ORF2 and codes for a small phosphoprotein of approximately 120 amino acid residues, which is required for viral infectivity in animals (Graff et al., 2005; Huang et al., 2007) and virus egress (Emerson et al., 2010; Yamada et al., 2009). The hepeviruses detected in rats and ferret contain an additional ORF4 in the 50 -region of the genome overlapping with ORF1; however, its expression and significance for virus replication is not known so far (Johne et al., 2010b; Raj et al., 2012). The genome organization of the completely sequenced HEV-like viruses is presented in Fig. 2. Although the genome organization is similar for all HEV-related agents, the total genome length and the size and distinct location of ORF1 to ORF3 is different (Supplementary Table 1). Especially, the length of the interspace region between ORF1 and ORF2/3 as well as the position of the initiation codon of ORF3 in relation to that of ORF2 may differ between the various hepeviruses, i.e. this codon of ORF3 is situated before or after that of ORF2. The ORF3 of the HEV-like virus detected in fish is located central within ORF2, which is remarkably different to the 50 -position in all other hepeviruses. A closer view at the ORF1-3 junction region is presented in Supplementary Fig. 1. 3. Host association and virus transmission The epidemiology of hepeviruses is complex and depends on the characteristics of the distinct virus as well as on environmental factors. Some of the hepevirus representatives show a narrow host

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Fig. 2. Genome organisation of members of the family Hepeviridae. The genomes of the hepeviruses have a size of 6–7 kb and contain the open reading frames (ORFs) 1–3. An additional putative ORF4 was predicted within the genomes of rat HEV and ferret HEV. The genome structures depicted are originating from genotype 1 (GT1; AF076239), genotype 4 (GT4; AB220977), rabbit HEV (GU937805), rat HEV (JN167537), ferret HEV (JN998607), wild boar HEV (AB573435), wild boar HEV (AB602441), bat HEV (JQ001749), avian HEV (GU954430) and trout HEV-like agent (NC015521).

range as assessed by molecular detection in their hosts and crossspecies infection trials, whereas others are capable to infect a wide range of animal species. Examples for host-specific hepeviruses are HEV genotype 1 and 2 strains, which seem almost exclusively infect humans. In contrast, HEV genotype 3 and 4 strains have been molecularly detected in humans, pig, wild boar, deer, mongoose, monkey and rat (Meng, 2013). Moreover, experimental infections of nude mice and gerbils were successful using HEV genotype 4 strains (Huang et al., 2009; Li et al., 2009). For many of the HEVlike agents identified recently, the distinct host range and the zoonotic potential are only scarcely known so far. Table 1 summarizes the reported host associations of mammal-associated hepeviruses. The known geographical distribution of mammalian and avian HEV and HEV-like viruses is shown in Fig. 3. One main transmission pathway of HEV is the faecal-oral route. Direct transmission of human HEV by contact with HEV-containing faeces may occur; however, faecally contaminated drinking water seems to represent the major vehicle for HEV genotype 1 and 2 transmission. In contrast, the transmission routes of the other hepeviruses are not so clearly elaborated. Zoonotic transmission of HEV genotypes 3 and 4 by contact of humans with pigs seems to occur frequently as shown by several seroprevalence studies (Krumbholz et al., 2012; Meng, 2011; Wilhelm et al., 2011; Bouwknegt et al., 2008; Galiana et al., 2008; Drobeniuc et al., 2001; Chaussade et al., 2013). However, the association of this transmission route with human disease is not well documented at present. Case control studies and single case molecular epidemiological reports support meat and meat products of infected pigs, wild boars and Sika deer as a source of human infection and disease (Meng, 2011). In addition, transmission of HEV by blood transfusion has been reported (Vollmer et al., 2012; Bajpai and Gupta, 2011). It is suspected that porcine and avian HEV are transmitted by contact and the faecal-oral route as it very rapidly spreads among animals in pig and chicken farms (Bouwknegt et al., 2011; Billam et al., 2005). Experimental and clinical investigations indicate that avian HEV might also be vertically transmitted (Guo et al., 2007; Troxler et al., 2014). However, oral

experimental infections of pigs have been turned out to be ineffective requiring high doses of infectious virus, whereas intravenous infection is highly effective (Bouwknegt et al., 2011). Further pig transmission experiments through the oral route demonstrated that the environment contributes to viral transmission (Andraud et al., 2013). The transmission routes of the other recently identified HEV-like agents are largely unknown. In the following chapters, the characteristics of the so far known HEV-like viruses and their involvement in diseases will be summarized. One focus of the chapters will be the natural host association and animal infection trials, which are used to uncover the host range and zoonotic potential of the viruses. An overview on mammalian reservoirs (Table 1) and the results of experimental cross-species infection trials (Fig. 4) of the HEV-like viruses is presented. Another focus of the specific chapters will be the genetic variability and phylogenetic relationship of the HEV-like agents. Sequence distance matrices of representatives of each virus are presented in Supplementary Table 2. Phylogenetic trees showing the relationship of selected strains of the known HEV-like viruses are shown in Fig. 5. 4. Mammalian HEV 4.1. Human genotypes 1 and 2 The HEV genome was first identified in a bile sample from macaques experimentally inoculated with stool suspensions from a HEV genotype 1-infected patient (Reyes et al., 1990; Tam et al., 1991). This strain originated from a hepatitis E outbreak in 1982 in Rangoon, Burma, and was subsequently designated as the Burmese isolate of HEV (Myint et al., 1985). Thereafter, many hepatitis E outbreaks caused by genotype 1 have been described from different countries of the Asian and African continent. One of the largest outbreaks with approximately 120,000 patients was recorded between 1986 and 1988 in the Xinjiang Uighur Autonomous region of China (Aye et al., 1992). More recently, in 2008, a large outbreak with estimated 23,915 affected persons and estimated 314 deaths

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R. Johne et al. / Infection, Genetics and Evolution 27 (2014) 212–229 Table 1 Molecular detection of natural hepevirus infections in non-human mammals. Order*

Family*

Primates

Cercopithecidae

Artiodactyla

Suidae Cervidae

Species

Acc. Number

Country of origin

Detected segment of genome

Source

Japanese macaque

Macaca fuscata

JQ026407

Japan

Full genome

Yamamoto et al. (2012)

Wild boar/ domestic pig Red deer European roe

Sus scrofa

AF011921

USA

ORF2 segment

Meng et al. (1997)

Cervus elaphus Capreolus capreolus Alces alces

EU718642 EU057982

Hungary Hungary

ORF2 segment ORF2 segment

Forgách et al. (2010) Reuter et al. (2009)

KF951328

Sweden

Full genome

Lin et al. (2014)

European elk (moose) Sika deer

Cervus nippon

AB189071

Japan

Full genome

Tei et al. (2003)

Aba leaf-nosed bat Great stripefaced bat Daubenton’s Myotis Bechstein’s Myotis Common serotine bat

Hipposideros abae Vampyrodes caraccioli Myotis daubentonii Myotis bechsteinii Eptesicus serotinus

JQ071861

Ghana

Drexler et al. (2012)

JQ001745

Panama

JQ001746

Germany

JQ001748

Germany

JQ001749

Germany

ORF1 segment (RdRp) ORF1 segment (RdRp) ORF1 segment (RdRp) ORF1 segment (RdRp) Full genome

Domestic ferret

JN998606

Netherlands

Full genome

Raj et al. (2012)

Mink

Mustela putorius Neovison vison

KC802093

Denmark

Krog et al. (2013)

Canidae

Red fox

Vulpes vulpes

KC692370

Netherlands

Herpestidae

Small Asian mongoose

Herpestes javanicus

AB368526

Japan

ORF1 segment (RdRp) ORF1 segment (RdRp) ORF2 segment

Lagomorpha

Leporidae

European rabbit

Oryctolagus cuniculus

FJ906894

China, France, USA

ORF2 segment, full genome

Zhao et al. (2009), Cossaboom et al. (2011), Izopet et al. (2012)

Rodentia

Muridae

Norway rat

GQ504010

Germany

Full genome

Johne et al. (2010b)

AB847305 KC465990

Indonesia China

KC465992

China

KC465994

China

Full genome ORF1 segment (RdRp) ORF1 segment (RdRp) ORF1 segment (RdRp)

Mulyanto et al. (2013) Li et al. (2013d)

Greater Bandicoot rat

Rattus norvegicus Rattus rattus Rattus rattoides losea Rattus flavipectus Bandicota Indica

Asian musk shrew

Suncus murinus

KC473531

China

Chiroptera

Hipposideridae Phyllostomidae Vespertilionidae

Carnivora

Mustelidae

Black rat

Soricomorpha

*

Soricidae

ORF1 segment (RdRp)

Drexler et al. (2012) Drexler et al. (2012) Drexler et al. (2012) Drexler et al. (2012)

Bodewes et al. (2013) Nidaira et al. (2012)

Li et al. (2013d) Li et al. (2013d) Guan et al. (2013)

Taxonomy according to Wilson and Reeder (2005).

was described from Nellore, India (Vivek et al., 2010). Additional outbreaks caused by genotype 1 have been reported from the African countries Algeria, Chad, Namibia and Sudan (van CuyckGandré et al., 1997; Maila et al., 2004; Nicand et al., 2005). HEV genotype 2 was first detected by analysis of samples from a hepatitis E outbreak with 223 affected persons in Mexico between 1986 and 1987, and was subsequently designated as the Mexican isolate of HEV (Velázquez et al., 1990; Huang et al., 1992). Thereafter, this genotype was relatively rarely identified; however, hepatitis E cases caused by genotype 2 have been reported recently from Namibia, Nigeria and Sudan (Maila et al., 2004; Nicand et al., 2005). The distribution of HEV genotype 1 and 2 strains among different countries in the world and the number of detected strains has been comprehensively reviewed by Okamoto (2007). The most important transmission pathway of HEV genotypes 1 and 2 is through faecally contaminated water supplies (Hazam et al., 2010; Ippagunta et al., 2007). Although person-to-person transmissions during outbreaks are considered to be less important, actual data from a large hepatitis E outbreak from Uganda indicate the effectiveness of hygienic measures in the household (Howard et al., 2010). The clinical presentation of hepatitis E patients is characterized by acute self-limiting hepatitis and the

major group affected by genotype 1 and 2 infections is in the range between 15 and 30 years of age (Scobie and Dalton, 2013). Exceptionally high mortality rates up to 26.9% have been described in pregnant women, with most deaths in the third trimester (Kumar et al., 2004; Labrique et al., 2012). However, the high mortality described during pregnancy is controversially discussed and appears to be unique for infection with HEV genotypes 1 and 2 (Scobie and Dalton, 2013; Labrique et al., 2012). So far, HEV genotypes 1 and 2 have only been detected in humans and in environmental samples contaminated with human excretions (Hazam et al., 2010; Ippagunta et al., 2007). Experimental transmissions of HEV to animals were first successful by inoculation of a genotype 1 strain to cynomolgus macaques and tamarins, which resulted in hepatitis and faecal virus shedding (Bradley et al., 1987). Thereafter, rhesus and cynomolgus monkeys as well as chimpanzees were used repeatedly as suitable animal models of human hepatitis E (Tsarev et al., 1994; Emerson et al., 2001; Yu et al., 2010). However, attempts to induce severe liver injury in pregnant rhesus monkeys using genotype 1 were unsuccessful (Tsarev et al., 1995). The Mexican genotype 2 strain was inoculated into cynomolgus monkeys and owl monkeys leading to seroconversion, virus propagation in the liver and disease in a

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A

Genotype 1 Genotype 2

B

Genotype 4

Genotype 3 Genotype 4

C

Fig. 3. Geographical distribution of hepeviruses. The distribution of human epidemic HEV genotypes 1 and 2 (A), zoonotic HEV genotypes 3 and 4 (B), and HEV-like viruses detected in rabbit, chicken, rats, bats, ferret, mink and fox (C) is shown.

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infection successful infection not successful divergent or partial results

GT1

Monkey

GT2

Pig

GT3

Rabbit (GT3)

Rabbit

Gerbil

GT4

Rat

rat HEV

Mouse

avian HEV

Chicken

Fig. 4. Summary of the results of experimental cross-species infection trials. Trials of experimental infections of an animal species (lower row) with a hepevirus (upper row) are shown by arrows. Green arrows indicate a successful infection as assayed by seroconversion and virus shedding. Red arrows show experiments, where no seroconversion and virus shedding could be observed after inoculation. Black arrows show trials with divergent results by different research groups or by use of different strains, trials with only partial indication of virus replication (e.g. seroconversion without virus shedding), or trials using only the viral genome for inoculation. Details of the indicated experiments are described in the text.

proportion of the animals (Ticehurst et al., 1992). Transmission of genotype 1 and 2 strains to pigs by intravenous inoculation was not successful (Meng et al., 1998a). Although an earlier study indicated susceptibility of laboratory rats to genotype 1 infection (Maneerat et al., 1996), recent trials to infect laboratory rats with genotypes 1 or 2 failed (Purcell et al., 2011; Li et al., 2013c). The human cell lines A549 and Hep G2/C3A have been shown to support replication of HEV genotype 1 strains, albeit with low efficiency (Emerson et al., 2006; Devhare et al., 2013). There is considerable genetic heterogeneity within HEV genotypes 1 and 2. Based on complete genome sequences, the nucleotide sequence divergence within genotype 1 strains reaches up to 13.2% (Oliveira-Filho et al., 2013). As only one genotype 2 strain has been completely sequenced so far, the range of maximum genomic nucleotide sequence differences could not be calculated. Using a 179-nt ORF2 sequence, the maximum divergence between genotype 1 strains was 13.4% and between genotype 2 strains 16.8% (Okamoto, 2007). Based on complete as well as partial genomic sequences, Lu et al. (2006) defined the HEV subtypes 1a–e and 2a–b. However, recent analyses of the genetic heterogeneity of known HEV strains could not confirm the presence of genetically distinct subtypes within the genotypes 1 and 2 (Oliveira-Filho et al., 2013; Smith et al., 2013). Nevertheless, it has been speculated that the genetic lineage of a strain may determine its virulence as genotype 1a strains from North India have been reported to cause acute self-limiting hepatitis, whereas infections with genotype 1c strains from the same region frequently caused fulminant hepatitis (Pujhari et al., 2010; Kumar et al., 2011). 4.2. Human zoonotic genotypes 3 and 4 HEV genotype 3 was discovered in 1997 when samples of domestic pigs from the USA were analyzed (Meng et al., 1997). Subsequently, an HEV strain closely related to this pig virus was detected in a hepatitis patient from the USA (Kwo et al., 1997; Schlauder et al., 1998). In the following years, many reports

described the detection of genotype 3 strains in humans and several animal species distributed worldwide, as reviewed elsewhere (Lu et al., 2006; Okamoto, 2007; Pavio et al., 2010; Purdy and Khudyakov, 2011). Genotype 3 is causing the majority of human infections in industrialized countries in Europe, Japan and the USA (Pavio et al., 2010; Meng, 2011, 2013). Based on database entries, Okamoto (2007) counted a total of 172 genotype 3 strains of humans and 511 genotype 3 strains of pigs derived from 22 different countries from the American, European, Asian and Oceania continents. Recently, genotype 3 strains have also been detected in pigs from the African continent (S de Paula et al., 2013). A fourth genotype of HEV was first identified in 1998 in samples from sporadic hepatitis cases from Taiwan and subsequently also in pigs from the same geographical region (Hsieh et al., 1998, 1999). At the same time, genotype 4 strains were identified in hepatitis patients from China and the complete genome of this genotype was sequenced (Wang et al., 1999, 2000). Genotype 4 strains are mainly confined to China, where they represent the most commonly detected HEV strains in humans and pigs (Okamoto, 2007; Geng et al., 2013b; Liu et al., 2012). However, genotype 4 strains are also endemic in Japan (Ohnishi et al., 2006; Sato et al., 2011). Moreover, this genotype has been recently identified in pigs from the Netherlands as well as in autochthonous human hepatitis E cases from France and Italy, which may indicate an actual spread of this genotype to Europe (Hakze-van der Honing et al., 2011; Jeblaoui et al., 2013; Garbuglia et al., 2013). Based on serological investigations it has been concluded that most human infections with HEV genotypes 3 and 4 are asymptomatic (Scobie and Dalton, 2013). Clinical courses mainly appear as sporadic acute hepatitis cases. However, small outbreaks, e.g. involving 11 hepatitis cases caused by genotype 3 on a cruise ship (Said et al., 2009) or 5 hepatitis cases caused by genotype 4 in a distinct region of Italy (Garbuglia et al., 2013), have also been described. In contrast to infections with genotypes 1 and 2, these genotypes mainly cause hepatitis in the middle-aged and elderly; additionally, men were found approximately 4-fold more often

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diseased than women (Scobie and Dalton, 2013). Although most patients show typical signs of viral hepatitis, a minority of patients has neurological disorders thus indicating neuropathogenicity of HEV genotype 3 (Kamar et al., 2011). In addition, this genotype has also been shown to cause chronic infections in immunocompromised transplant patients (Kamar et al., 2013). The major transmission routes of HEV genotypes 3 and 4 are suspected to be zoonotic and foodborne. The evidence for these transmission pathways has been comprehensively reviewed recently (Pavio et al., 2010; Meng, 2011, 2013). In industrial countries in Europe, Japan and the USA, domestic pigs have been frequently

found to contain HEV-specific antibodies underlining the role of pigs as a source of HEV infection (Baechlein et al., 2010; Dremsek et al., 2013; Krumbholz et al., 2013; Pavio et al., 2010). Direct molecular or indirect epidemiological evidence for foodborne route of transmission of genotype 3 comes from case studies in Japan and France showing that ingestion of HEV-containing meat or sausages prepared from wild boar, sika deer or pig lead to hepatitis E in humans (Li et al., 2005; Tei et al., 2003; Colson et al., 2010). Hepatitis E cases due to ingestion of pork meat and entrails containing genotype 4 have been described recently from Japan (Miyashita et al., 2012). A systematic review on transmission routes of

A 267nt ORF1 GT3-JDEER-Hyo03L-deer-AB189071 GT3-Meng-pig-AF082843 GT3-wbGER27-wild boar-FJ705359

HEV3

rabbitHEV-GDC9-rabbit-FJ906895

85/0.91

rabbitHEV-TLS-18516-human-JQ013793 GT3-HEV RKI-human-FJ956757 GT4-wbJGF 08-1-wild boar-AB602440 GT4-SAAS-FX17-pig-JF915746 78/0.83

HEV4

GT4-T1-human-AJ272108 GT4-WH09-pig-GU188851

-/-

Orthohepevirus

wbHEV-JBOAR135-Shiz09-wild boar-AB57343 60/0.75

HEV5

wbHEV-wbJNN 13-wild boar-AB856243 wbHEV-wbJOY 06-wild boar-AB602441

-/-

56/0.70

HEV2

GT2-Mexican-human-M74506 GT1-T3-human-AY204877

91/0.93 100/0.99

HEV1

GT1-Burmese(SAR-55)-human-M80581 GT1-Hyderabad-human-AF076239

moose HEV fox HEV mink HEV

mooseHEV-AlgSwe2012-moose-KF951328 foxHEV-Fox3-fox-KC692370 -/-

100/0.99

minkHEV-345-3-mink-KC802092 minkHEV-1119-3-mink-KC802090

98/0.93 74/0.68

ferretHEV-FRHEV20-ferret-JN998607 100/0.99 98/0.92

ferret HEV

ferretHEV-FRHEV4-ferret-JN998606

Rocahepevirus

ratHEV-R63-rat-GU345042 ratHEV-CHZMRat-E-510-rat-KC465994 99/0.98

(unclassified)

ratHEV-CHZ-sRatE-1129-shrew-KC473530

rat HEV

ratHEV-ESOLO-014SF-rat-AB847306 ratHEV-Vietnam-105-rat-JX120573 ratHEV-CHZCRat-E-321-rat-KC465990 ratHEV-CHZ-sRatE-1107-shrew-KC473529 batHEV-NMS098B-bat-JQ001746

bat HEV

Chiropteranhepevirus

avian HEV1 avian HEV2 avian HEV3 avian HEV4

Avihepevirus

cuhroat trout virus

Piscihepevirus

batHEV-BS7-bat-JQ001749 99/0.99

batHEV-Pan926-bat-JQ001745 batHEV-G19E36-bat-JQ001744 avianHEV-06-561-chicken-AM943647

80/0.87

avianHEV-USA-chicken-AY535004 100/0.99

avianHEV-05-5492-chicken-AM943646 avianHEV-HU-16773-chicken-JN997392 avianHEV-TWNaHEV-chicken-KF511797 fishHEV-Heenan88-trout-NC 015521

0.1

Fig. 5. Phylogenetic relationships of hepeviruses. Phylogenetic trees are based on (A) a 267 nucleotide sequence from the RdRp-coding region within the ORF1 from 40 hepevirus strains or (B) the entire genome sequences of 25 hepevirus strains. Trees were reconstructed with Neighbor-Joining and Bayesian algorithms analogous to Fink et al. (2007, 2010) and Johne et al. (2012). Support for nodes is given as percent bootstrap from 5000 replicates before the slash and posterior probability after the slash. Hyphens indicate support values below 0.5 and the scale bar indicates the number of nucleotide substitutions per site. The branches are labeled with the genotype or virus designation, strain designation, host species, and GenBank accession number. A preliminary grouping into virus species and genera as proposed by the authors is indicated on the right.

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B complete genomes GT3-JDEER-Hyo03L-deer-AB189071 GT3-Meng-pig-AF082843 GT3-wbGER27-wild boar-FJ705359 GT3-HEV RKI-human-FJ956757

100/1.0

HEV3

rabbitHEV-TLS-18516-human-JQ013793 rabbitHEV-GDC9-rabbit-FJ906895 70/0.63

GT4-T1-human-AJ272108 100/1.0

HEV4

GT4-swGX32-pig-EU366959 GT4-wbJGF 08-1-wild boar-AB602440

Orthohepevirus

98/0.65

wbHEV-JBOAR135-Shiz09-wild boar-AB57343

100/1.0 98/0.93

wbHEV-wbJNN 13-wild boar-AB856243

HEV5

wbHEV-wbJOY 06-wild boar-AB602441

HEV2

GT2-Mexican-human-M74506

91/0.63

GT1-Burmese(SAR-55)-human-M80581

99/0.85 100/1.0

GT1-Hyderabad-human-AF076239 ferretHEV-FRHEV20-ferret-JN998607

HEV1 ferret HEV

ratHEV-R63-rat-GU345042

100/1.0 100/1.0

ratHEV-ESOLO-014SF-rat-AB847306

rat HEV

ratHEV-Vietnam-105-rat-JX120573

bat HEV avianHEV-06-561-chicken-AM943647 avian HEV1 avianHEV-USA-chicken-AY535004 avian HEV2 avianHEV-05-5492-chicken-AM943646 avian HEV3 avianHEV-TWNaHEV-chicken-KF511797 avian HEV4 cuhroat trout virus fishHEV-Heenan88-trout-NC 015521 batHEV-BS7-bat-JQ001749

93/0.96 100/1.0

Rocahepevirus Chiropteranhepevirus Avihepevirus Piscihepevirus

0.2 Fig. 5 (continued)

autochthonous HEV infections identified the zoonotic transmission as likely, but person-to-person transmission as too inefficient to cause clinical disease (Lewis et al., 2010). However, there was no evidence for one main specific transmission route of HEV infection or one risk factor for hepatitis E; therefore, other routes, e.g. environmental transmission or transmission by blood and blood products, may also be important (Lewis et al., 2010). HEV associated with porcine-derived products used in human medicine may also pose a risk of virus transmission as recently suggested for porcine heparin products (Crossan et al., 2013). The host range of HEV genotypes 3 and 4 is broad. Natural infection with genotype 3 has been molecularly detected in representatives of the order Artiodactyla (pig, wild boar, deer), in mongoose, monkey and rats (Pavio et al., 2010; Yamamoto et al., 2012; Lack et al., 2012; see Table 1). Genotype 4 has been repeatedly found in pigs and wild boars in the endemic countries, and single reports of its molecular detection in cattle and sheep exist (Meng, 2013). Experimental inoculation studies with a pig-derived genotype 3 strain in rhesus monkeys and a chimpanzee confirmed the capability of its zoonotic transmission (Meng et al., 1998b). Rhesus monkeys have also been successfully infected with genotype 4 (Arankalle et al., 2006). Pigs have repeatedly been shown to be susceptible for experimental infection by intravenous inoculation with genotype 3 and 4 strains (Meng et al., 1998a; Feagins et al.,

2008). Efforts to infect laboratory rats with genotype 3 were not successful (Purcell et al., 2011; Li et al., 2013a,c). Injection of transcripts of a genotype 4 cDNA into the liver of rats led to transient seroconversion (Zhu et al., 2013). This genotype was also shown to be infective for Balb/c nude mice (Huang et al., 2009). Experimental infection of rabbits with genotype 3 and 4 strains resulted in seroconversion; however, virus shedding was dependent on the strain used (Cheng et al., 2012). Mongolian gerbils have also been reported to be susceptible to experimental infection with genotype 4 (Li et al., 2009). Several cell culture systems, especially the human hepatocellular carcinoma cell line PLC/PRF/5 and the human lung carcinoma cell line A549, have been repeatedly shown to support the replication of HEV genotype 3 and 4 strains, although with rather low efficiency (Okamoto, 2013). In addition, three-dimensional (3D) cell culture systems and porcine cell cultures have been used for isolation of genotype 3 strains (Berto et al., 2013a,b; Rogée et al., 2013). Distinct patient-derived genotype 3 strains carrying insertions in their hypervariable ORF1 region have recently been shown to replicate more efficient in cell culture (Shukla et al., 2011, 2012; Johne et al., 2014). A high degree of sequence variability has been documented for genotype 3 and 4 strains. Based on complete genome sequences, nucleotide sequence divergences of up to 27.1% were found for genotype 3 and 19.9% for genotype 4 strains (Oliveira-Filho et al.,

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2013). In the subtype classification system set up by Lu et al. (2006), the genotypes 3a–j and 4a–g have been defined. However, recent analyses using more strains and larger genomic regions could not confirm this subgrouping. Instead, grouping of genotype 3 into the three subtypes 3.1, 3.2 and 3.3 (including the rabbit HEV, see below) was suggested, whereas no reliable subtypes could be defined for genotype 4 (Oliveira-Filho et al., 2013). In another recent approach based on 108 complete HEV genomes, no consistent criteria could be defined for the assignment of subtypes for HEV genotypes 3 and 4 (Smith et al., 2013). Some studies tried to link specific nucleotide substitutions present in genetically divergent genotype 3 and 4 strains to the severity of the disease caused by them (Inoue et al., 2006; Takahashi et al., 2009; Fu et al., 2011). By comparison of genome sequences of strains derived from mild and severe clinical cases, two silent mutations in genotype 4 strains and one amino acid exchange within the helicase domain of genotype 3 strains have been identified as putative indicators of increased virulence (Inoue et al., 2006; Takahashi et al., 2009). 4.3. Rabbit HEV Rabbit HEV was first detected in farmed rabbits in China in 2009 (Zhao et al., 2009). Subsequently, the virus was detected in farmed rabbits from other regions of China (Geng et al., 2011, 2013a; Wang et al., 2013), Mongolia (Jirintai et al., 2012), France (Izopet et al., 2012) and the USA (Cossaboom et al., 2011, 2012a). Rabbit HEV was also demonstrated in wild rabbits from France (Izopet et al., 2012). An HEV strain (designated TLS-18516) closely related to rabbit HEV was detected in a human hepatitis E patient from France, indicating a possible zoonotic transmission of rabbit HEV to humans (Izopet et al., 2012). Experimental inoculation of rabbits with rabbit HEV led to seroconversion, virus shedding in the faeces, viraemia and elevated level of liver enzymes (Ma et al., 2010; Cheng et al., 2012). Pigs intravenously inoculated with rabbit HEV strains from China and the USA developed transient viremia and sporadic virus shedding, thus indicating a zoonotic potential of the virus (Cossaboom et al., 2012b). Recently, cynomolgus macaques were experimentally infected with rabbit HEV. The infected animals showed elevated liver enzymes, viremia, virus shedding in faecal specimens, and seroconversion (Liu et al., 2013). Jirintai et al. (2012) reported successful propagation of rabbit HEV in human liver- and lung-derived carcinoma cell cultures. Genetic analyses of rabbit HEV strains indicate a close relationship with HEV genotype 3 strains (Zhao et al., 2009; Geng et al., 2011, 2013a; Izopet et al., 2012). However, all known rabbit HEV strains form a cluster separated from HEV genotype 3 in phylogenetic trees (Lhomme et al., 2013; as shown for the complete genome-derived phylogenetic tree; see Fig. 5B), thus indicating a separate evolution of the viruses in the different hosts. In addition, all rabbit HEV strains analyzed so far including the human rabbit HEV-like strain TLS-18516 have a 93-nucleotide insertion in the X domain of the ORF1, which is not found in HEV genotype 3 as well as genotype 1, 2 and 4 strains (Lhomme et al., 2013). By complete genome analysis, nucleotide sequence identities between 80.3% and 85% were found within the group of rabbit strains and strain TLS-18516, whereas the identities of this group compared to genotype 3 strains ranged from 76.1% to 78.2% (Izopet et al., 2012). Future analysis of complete genomes of rabbit HEV from different geographical regions should verify if rabbit HEV represents a separate genotype. 4.4. Novel genotypes in wild boar In 2010, HEV strain JBOAR135-Shiz09, which is only distantly related to genotypes 1–4 was identified in a wild boar in Japan

(Takahashi et al., 2010). Subsequently, another strain, designated as wbJOY_06 and also divergent from genotypes 1–4, was reported from a wild boar sample from another region in Japan (Sato et al., 2011). Thereafter, during a large molecular survey including 566 wild boars captured in Japan, a third unusual HEV strain designated wbJNN_13 was identified in a single animal (Takahashi et al., 2014). The entire genomes of all three strains have been sequenced and compared to each other as well as to the known HEV genotypes. These wild boar-derived strains showed nucleotide sequence identities between 71.8% and 77.6% to the established HEV genotypes 1–4, and between 78.1% and 80.4% to each other (Takahashi et al., 2014). From further genetic analyses, it was suggested to place the novel strains JBOAR135-Shiz09 and wbJOY_06 either into two distinct novel genotypes 5 and 6 (Smith et al., 2013), or both into the novel genotype 5 (OliveiraFilho et al., 2013). The classification of strain wbJNN_13 remains unsolved as the original authors claimed for the definition of consensus criteria before classification into new genotypes (Takahashi et al., 2014). As all three strains have been detected only once in single animals, the geographical distribution, degree of variation as well as the host range and zoonotic potential of these novel HEV types remain unknown. The presence of multiple genotype 3 and 4 strains as well as the three novel divergent strains in wild boars indicates that this animal species represents a major reservoir for HEV. 4.5. Novel HEV-related virus in moose A recent real-time RT-PCR based screening of six liver and kidney samples of moose (Alces alces) from Sweden showed a positive result (Lin et al., 2014). The determination of a 5.1 kb segment of the genome containing a part of ORF1 and the entire ORF2 and ORF3 sequences demonstrated a genome organization typical for HEV. The general nucleotide sequence similarity to the HEV genotypes 1–4 was only 37–63% and a highly divergent ORF3 sequence was evident. Phylogenetic analysis revealed a shared ancestor with the genotypes 1–4 and new wild boar strains, independently if the tree was reconstructed on different ORF1 or ORF2 regions or both regions combined. The sequence divergence between the moosederived sequences and those from deer-derived genotype 3 may indicate a specific association of the detected strain with the moose. Alternatively, the finding might be explained by a spillover infection from a so far not identified reservoir. In addition, it remains to be investigated whether this novel strain has a zoonotic potential. Importantly, moose meat is frequently consumed in Scandinavia. Although the sample originated from a diseased animal, the carcass was reported to be severely decomposed and therefore not suitable for histopathological inspection. Interestingly, the animal was found to be emaciated, had a myocardial injury and infections by Anaplasma phagocytophilum and other agents (Lin et al., 2014). 4.6. Rat HEV The development of a hepevirus-specific broad-spectrum RTPCR resulted in the first molecular identification of a novel HEVrelated agent in Norway rats (Rattus norvegicus) from Hamburg, Germany (Johne et al., 2010a). A primer walking-based approach resulted in the determination of the entire genome sequence of two strains, which showed genome sequence similarities of only 49.5–55.9% to avian HEV strains and HEV genotype 1–4 strains, respectively (Johne et al., 2010b). These investigations revealed a genome structure similar to that determined for genotypes 1–4, except the existence of three additional putative open reading frames (Johne et al., 2010b). Further studies proved one of these putative ORFs, which is overlapping with the 5’-region of ORF 1

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and designated as ORF 4, to be conserved between HEV strains from rats in Germany and Vietnam (Johne et al., 2012; Li et al., 2013b). Currently, several strains of the virus have been molecularly detected at different sites in Germany (Johne et al., 2010b, 2012), Denmark (Wolf et al., 2013), Vietnam (Li et al., 2013b), Indonesia (Mulyanto et al., 2013), China (Li et al., 2013d) and the USA (Purcell et al., 2011). The multiple detection of distinct HEV strains in R. norvegicus, R. rattus and other rat species resulted in the assumption of a rat host specificity of this virus type, which was therefore designated as rat HEV (Johne et al., 2010b, 2012; Mulyanto et al., 2013; Li et al., 2013b). However, rat HEV-related sequences have been recently detected in the Greater Bandicoot rat (Bandicota indica) and the Asian musk shrew (Suncus murinus), which might indicate a broader host range or spillover infections (Li et al., 2013d; Guan et al., 2013). Previous detection of HEVspecific antibodies in additional rodent species may indicate the existence of further, antigenically related HEV strains (KabraneLazizi et al., 1999; Favorov et al., 2000; Arankalle et al., 2001; Hirano et al., 2003; Vitral et al., 2005). The zoonotic potential of rat HEV is controversially discussed. Experimental infections of rhesus monkeys (Purcell et al., 2011) and domestic pigs (Cossaboom et al., 2012b) with rat HEV failed. In contrast, inoculation of the virus into laboratory rats led to seroconversion and virus shedding (Purcell et al., 2011; Li et al., 2013c). Although obvious clinical symptoms were not recorded, a hepatotropism of the virus was found in experimentally and naturally infected rats (Li et al., 2013c; Johne et al., 2010b). Inoculation of rat HEV into immunosuppressed nude rats led to persistent infections (Li et al., 2013c). In addition to experimental cross-species infection experiments, serological tools capable of differentiating rat HEV-specific antibodies from those specific for HEV genotype 3, have been developed in order to assess the zoonotic potential of rat HEV (Johne et al., 2011, 2012). In a serosurvey of blood donors and forestry workers a few sera of forestry workers showed an almost exclusive reactivity with the rat HEV-derived antigen (Dremsek et al., 2012). A higher reactivity with recombinant rat HEV antigen than with the corresponding HEV genotype 3 antigen has also been demonstrated for a proportion of porcine sera collected in Germany (Krumbholz et al., 2013). These results might be explained by rare human and pig infections by rat HEV, or by infections with an antigenically related hepevirus. The genetic diversity of rat HEV has been analyzed in several studies (Johne et al., 2010b, 2012; Wolf et al., 2013; Li et al., 2013b; Mulyanto et al., 2013; Purcell et al., 2011). A recent analysis including 10 complete genome sequences of rat HEV indicated the existence of 3 distinct genetic groups of rat HEV (Mulyanto et al., 2014). The genome sequence identity within the groups ranged from 86.4% to 95.2%, whereas those between the groups ranged from 76.4% to 80.9%. A geographical clustering was evident for rat HEV strains derived from different sites in Germany (Johne et al., 2012). 4.7. Carnivore HEV: strains detected in ferret, fox and mink First molecular evidence of carnivore-borne hepeviruses was obtained for household pet ferrets (Mustela putorius) by a next generation sequencing (NGS) approach (Raj et al., 2012). A similar approach on faecal samples from red foxes resulted in the identification of a distinct hepevirus strain designated fox hepevirus (Bodewes et al., 2013). Most recently, an additional hepevirus was identified in farmed mink from Denmark using a broad-spectrum RT-PCR, but was absent in wild-living animals (Krog et al., 2013). So far, only the complete genome of ferret HEV was determined, whereas from mink hepevirus only a short-sized segment of ORF1 (261 nt), and for fox hepevirus segments of ORF 1 (362 nt) and ORF2 (295 nt) have been determined.

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Multiple detections of ferret HEV in ferrets from different geographical locations confirmed ferrets as most likely reservoirs of this virus. Similarly, mink HEV was detected in four animals from different geographical origin, suggesting the mink being the reservoir of another carnivore hepevirus. The detection of fox HEV in faecal samples of 2 out of 13 foxes from a region in the Netherlands may also indicate the fox being the reservoir of this virus. However, this novel hepevirus may also originate from a prey species, e.g. a so far unknown rodent-borne hepevirus, which only passaged the gastrointestinal tract of the foxes. Future investigations on field samples, experimental infection trials and epidemiological studies are necessary to clarify the distinct host range and zoonotic potential of these novel viruses. It is currently unknown if infections with the carnivoreassociated hepeviruses causes clinical signs or not in their putative reservoirs. The HEV-infected household pet ferrets were reported to show no overt clinical signs (Raj et al., 2012). The two HEVpositive foxes were collected during monitoring on parasites, but no information about their health conditions were reported (Bodewes et al., 2013). All of the HEV-positive minks had histories of diarrhoea in the herd; however, this might be explained by other detected pathogens, such as mink enteritis virus or Aleutian mink disease virus (Krog et al., 2013). Phylogenetic analyses of the ORF1 fragment of the three carnivore hepeviruses confirmed their distinctness (Krog et al., 2013). Interestingly, they are most closely related to rat HEV strains with 69–76% nucleotide sequence identity, forming a separate branch containing rat HEV and carnivore HEV in a hepevirus phylogenetic tree (Krog et al., 2013; see Fig. 5). 4.8. Bat HEV The initial description of novel hepeviruses in bats was based on a screening of 2624 faecal, 1173 blood and 72 liver samples from 85 bat species using a hepevirus broad-spectrum RT-PCR (Drexler et al., 2012). This investigation resulted in the detection of 7 positive samples originating from five different bat species belonging to three families of the order Chiroptera (Table 1). The complete hepevirus genome was determined from one Common serotine bat (Eptesicus serotinus) captured in Germany. In addition to ORFs 1–3, an additional putative ORF designated as ORF NX was identified at a similar position as ORF4 in rat HEV and ferret HEV. However, the deduced amino acid sequence identity between these ORFs was only 30.5%, thus questioning a similar function (Drexler et al., 2012). The distinct host ranges of the bat hepeviruses are not known so far. The low frequency of bat HEV detection in bats may be in favour for spillover infections from other animal reservoirs. However, the phylogenetic analysis of the detected strains indicated specific clustering according to their origin from the host bat species, which would support a reservoir function for some bat species for these novel HEV strains. It is not known whether bat HEV infection causes any disease in bats, although high viral loads were found especially in the liver (Drexler et al., 2012). Currently, there are no data available on the ability of experimental transmission of bat HEV strains to bats or other mammals. A PCR screening of pooled plasma samples from 93,146 blood donors from Germany and pooled samples from 453 otherwise healthy HIV-infected patients from Cameroon failed to detect any bat HEV-related RNA (Drexler et al., 2012). This finding may suggest that bat HEV causes no or very rarely zoonotic infections in humans. A comparison of the ORF1 nucleotide sequences of a completely sequenced bat HEV strain revealed only 48.1–52.3% similarity with that of genotypes 1–4, rat HEV and avian HEV (Drexler et al., 2012). Based on a comparison of a 108 amino acid ORF1-derived sequence, a high degree of divergence was observed between the

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bat hepeviruses, leading to the conclusion that the detected seven bat HEV strains may be grouped into 3 or 4 different genotypes (Drexler et al., 2012).

5. Avian HEV A disease in broiler breeders caused by avian HEV and designated as Big Liver and Spleen Disease (BLSD) was first reported from Australia in 1988, although the etiologic agent was not identified at this time-point (Handlinger and Williams, 1988). A similar disease was later on described in layer chicken in North America, which was designated as hepatitis-splenomegaly syndrome (HSS) (Ritchie and Riddell, 1991). Although a viral aetiology of the diseases was assumed for a longer time, the aetiological agent was first identified in 1999, when a short part of the genome of avian HEV could be sequenced from samples of chickens infected with the BLSD-causing agent (Payne et al., 1999). Later on, about half of the genome of avian HEV was sequenced from bile samples of chickens with HSS (Haqshenas et al., 2001). The whole genome sequence of the agent was determined in 2004 indicating only low genome sequence similarities of about 50% to HEV genotype 1–4 strains (Huang et al., 2004). Meanwhile, several studies indicate a broad distribution of avian HEV infections in chickens from several parts of the world. In the USA about 71% of chicken flocks and 30% of chickens were positive for antibodies against avian HEV (Huang et al., 2002). Nearly all of the 61 breeder and layer flocks tested in Taiwan were positive for avian HEV with a seroprevalence of 40.6% (Hsu and Tsai, 2014). Similarly, a high number of positive flocks (26/29) with 20–80% of the birds being seropositive was recorded in Spain (Peralta et al., 2009) and Korea where 57% of the flocks and 28% of the chickens had antibodies against avian HEV (Kwon et al., 2012). In China all tested 9 breeder flocks, as young as 3 weeks of age, and 36.9% of the birds were positive (Zhao et al., 2013). So far, clinical cases of BLSD or HSS were only reported in layers or broiler breeders (Agunos et al., 2006; Handlinger and Williams, 1988; Ivanics et al., 2011; Massi et al., 2005; Morrow et al., 2008). The disease caused by avian HEV infection is characterized by a drop in egg production up to 20%, which might coincide with a slight increase of the weekly mortality reaching 1%. However, numerous reports describe the presence of avian HEV in chickens without any disease (Huang et al., 2002; Sun et al., 2004; Peralta et al., 2009; Todd et al., 1993). In post mortem investigations, a severe swelling of the liver and spleen are the most obvious lesions, which can be noticed in up to 20% of the birds. Regression of the ovaries explains the noticed drop in egg production. Histological lesions are characterized by accumulation of amyloid in livers, vasculitis and necrotic, haemorrhagic, hepatomegalic hepatitis (Tablante et al., 1994). Whereas pathomorphological and histological findings were confirmed in experimental studies with chickens, clinical signs could not be reproduced, leading to the assumption that other co-factors are needed for development of the disease. This is also supported by the fact that no differences were noticed between viruses isolated from diseased and non-diseased birds after infection of specific-pathogen-free (SPF) chickens (Billam et al., 2009). Following oronasal infection of SPF chickens, virus excretion in the faeces could be demonstrated up to 8 weeks in the presence of IgG antibodies in the serum (Billam et al., 2005). In different studies, effective spread of the virus to in-contact birds could be shown following a natural route of infection (Clarke et al., 1990; Crerar and Cross, 1994; Sun et al., 2004). It could be demonstrated that in addition to the liver the gastrointestinal tissues, from duodenum until rectum, are sites of viral replication supporting faecaloral transmission (Billam et al., 2008). Also, infectious cDNA clones

were successfully established and infectivity was demonstrated in SPF chickens infected with virus recruited from birds injected intrahepatically with RNA transcripts (Huang et al., 2005; Kwon et al., 2011). Such constructs also bear the option to study the replication of avian HEV in vitro via transfection of a chicken hepatoma (LMH) cell line, although spread of virus was not observed (Kenney et al., 2012). Efficient multiplication of avian HEV outside its host is so far restricted to chicken embryos infected intravenously (Payne et al., 1993). Based on results of virus detection or presence of viral nucleic acid, it has to be concluded that avian HEV infections are limited to chickens. Single studies in China report the presence of antiHEV IgG in ducks and pigeons (Zhang et al., 2008). Experimental intravenous infection of turkeys with avian HEV obtained from chickens induced seroconversion, viraemia and faecal virus shedding in the majority of birds (Sun et al., 2004). One out of nine incontact birds seroconverted; however, without confirmation of viraemia and virus excretion. Furthermore, lesions in the infected turkeys were not demonstrated. A cross-species infection experiment was also performed by intravenous inoculation of avian HEV into two rhesus monkeys (Huang et al., 2004). In these animals, no seroconversion, viraemia or faecal virus shedding was observed indicating a low zoonotic risk of avian HEV, if present at all. The complete or nearly complete genome sequences of avian HEV from the USA, Australia, Hungary, China, Korea and Taiwan have been reported, showing nucleotide sequence diversities between avian HEV strains up to 18.2% (Banyai et al., 2012; Bilic et al., 2009; Hsu and Tsai, 2014; Huang et al., 2004; Kwon et al., 2012; Zhao et al., 2010). Although the general genome organization of avian HEV is similar to that of HEV genotype 1–4 strains, the genome length is about 600 nucleotides shorter and the genome sequence identity is only about 50%. In an initial study performed by Bilic et al. (2009), three different avian HEV genotypes with a certain geographic distribution were noticed based on sequence relationship between isolates from Australia, America and Europe. Although the existence of different genotypes is also supported by later studies, their geographical clustering is not clear and different genotypes might appear in the same country or region (Marek et al., 2010; Sprygin et al., 2012). Recently, a putative new genotype of avian HEV has been detected in Hungary and Taiwan (Banyai et al., 2012; Hsu and Tsai, 2014).

6. Fish hepevirus Cutthroat trout virus (CTV), a virus that was initially isolated in 1988 from a cutthroat trout (Oncorhynchus (O.) clarki) (Hedrick et al., 1991), was recently found to have significant similarities to mammalian and avian hepeviruses regarding morphology and genome organization (Batts et al., 2011). Using a Chinook salmon embryo-derived cell culture system, a slow and focal cytopathic effect could be demonstrated upon CTV replication. Subsequent studies in this cell culture system confirmed the presence of CTV in ovarian fluids of different trout species (family Salmonidae) including cutthroat trout (O. clarki), rainbow trout (O. mykiss), brown trout (Salmo trutta) and brook trout (Salvelinus fontinalis) (Hedrick et al., 1991). Surveillance efforts resulted in the detection of a broad geographical distribution of this virus in the western part of the USA, including additional trout species, such as O. gilae, O. apache and O. aguabonita (Batts et al., 2011). Although CTV shows similarities in genome organization with other hepeviruses, the genome sequence similarity of the prototype CTV isolate to HEV genotypes 1–4, rat HEV and avian HEV was found to be only between 38% and 49% (Batts et al., 2011). The amino acid sequence similarity was found to be the highest within the ORF1-encoded polyprotein reaching 26–27% (Batts

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et al., 2011). The ORF 3 of CTV is located central within ORF2, which is remarkably different to the 50 -position in all other hepeviruses. In addition, the protein encoded by ORF3 shows only 13– 16% amino acid sequence similarity to that of HEV genotypes 1–4 (Batts et al., 2011). Based on the rather high diversity of the CTV genome it was questioned by some authors, whether the HEV-like virus from fish should be grouped into the family Hepeviridae or not (Oliveira-Filho et al., 2013). Experimental infections of different trout and salmon species with CTV have not been associated with mortality or microscopic pathology, although the virus could be re-isolated from some of the animals (Hedrick et al., 1991). Molecular epidemiological investigations suggest a long-term maintenance of the virus in populations, although a life-long carrier state and vertical transmission have not been experimentally demonstrated for CTV (Batts et al., 2011). The ability of CTV to propagate at high titers in cell culture and in vivo, and the availability of a persistently infected cell line as well as susceptible animal models were prerequisites for the screening of putative antiviral drugs (Batts et al., 2011). Indeed, Chinook salmon embryo cells were recently employed to demonstrate antiviral effects of different substances, such as ribavirin, testosterone and 17b-estradiol (Debing et al., 2013). Analysis of a 262 nt region of the helicase-encoding ORF1 region of 63 CTV isolates from different trout species and locations indicated only a low degree of heterogeneity, with sequence divergences ranging from 0% to 8.4% (Batts et al., 2011). No obvious clustering pattern with regard to geographical origin or host species was observed. A previously described virus isolate from an Atlantic salmon Salmo salar in Canada (Kibenge et al., 2000) was found to have a high nucleotide sequence similarity of 93% with CTV (Batts et al., 2011).

7. Taxonomic considerations According to the actual taxonomy stated by the International Committee on Taxonomy of Viruses (ICTV) (Meng et al., 2012), the family Hepeviridae comprises only the single genus Hepevirus. This genus comprises the single species Hepatitis E virus, which is formed by HEV 1–4 (corresponding to genotypes 1–4). Rabbit HEV is considered as belonging to genotype 3. Rat HEV is listed as a tentative additional species of the genus Hepevirus. The species Avian hepatitis E virus, which is formed by avian HEV 1–3 (corresponding to avian genotypes 1–3), is contained within the family Hepeviridae, but not assigned to a genus so far. Other viruses, which have been discovered only recently, are not considered in the classification scheme so far. Therefore, the new viruses derived from wild boar, ferret, mink, moose, fox, different bat and salmonid fish species are still waiting for their taxonomic classification. Moreover, it could be expected that a general review of the current classification scheme within the family Hepeviridae will be necessary based on the growing number of novel HEV-like strains. Several phylogenetic studies have been performed recently in order to elucidate the distinct relationships between the currently known HEV strains and to suggest their classification. In an approach using comparison of concatenated ORF1/ORF2-derived amino acid sequences of 180 complete HEV genomes excluding hypervariable regions, Smith et al. (2013) divided the HEV strains closely related to those infecting humans into six genotypes: the well established genotypes 1–4 as well as the two additional genotypes from wild boar. The rabbit HEV occupied an intermediate position and it could not be decided whether the rabbit strains belong to genotype 3 or form a separate genotype. The existence of distinct subtypes was not supported. However, the definition of four HEV species comprising viruses infecting (i) humans and

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pigs, (ii) rats and ferret, (iii) different bat species, and (iv) chicken was suggested within the genus Hepevirus. The HEV-like virus of fish was considered to represent a second genus. Oliveira-Filho et al. (2013) compared the nucleotide sequences of complete genomes and the ORF 2 coding region of 196 HEV isolates. By this, HEV genotypes 1–4 were confirmed and the two wild-boar derived sequences were considered as an additional genotype 5. The existence of the subtypes 3.1, 3.2 and 3.3 – the latter containing the rabbit HEV strains – was evident within genotype 3. It was suggested that the viruses infecting rats, ferret, chicken and bats should be grouped into 4 separate genera. It was questioned, whether the HEV-like virus from fish should be grouped into the family Hepeviridae or not. Meng (2013) proposes the classification into 6 genotypes within a tentative genus Orthohepevirus, which contains the established genotypes 1–4, genotype 5 formed by one wild boar isolate (only one of the wild boar isolates was known at this time-point), and genotype 6 formed by rat and ferret isolates. In addition, the generation of the tentative genera Avihepevirus (with 3 genotypes), Piscihepevirus (containing the fish HEV) and Chiropteranhepevirus (containing the bat HEV) was suggested. The rabbit isolates are considered as a member of genotype 3. In contrast, based on nucleotide sequence distances and the presence of a unique insertion within ORF1, Lhomme et al. (2013) suggested grouping of the rabbit HEV strains into a separate genotype different from genotype 3. Fig. 5A and B shows phylogenetic trees based on an analysis following the approaches already used in the studies by Johne et al. (2010b, 2012) for HEV (substitution model testing, alternative algorithms NJ, Bayesian, etc.) and additional tests (analogous to Fink et al., 2007, 2010). The topologies are consistent with our earlier phylogenetic analyses of HEV (Johne et al., 2010b, 2012), and they match almost completely between full genomes and a short 267 nt fragment of ORF1. Distinct clades are visible for HEV genotypes 1–4, ferret and rat HEV, avian HEV, bat HEV and CTV. The proposed HEV5 is a particular case because it is only a monophyletic clade in the analyses of the complete genomes (Fig. 5B) whereas it appears paraphyletic in phylogenies reconstructed from the short ORF1 fragment (Fig. 5A). However, it should be noted that the support values for the paraphyletic position of the sequence wild boar AB57343 are very low (32% and 0.45) based on the short fragment (Fig. 5A); in contrary, support for a monophyletic clade HEV5 is very strong based on full genome data (98%; 0.93). In addition, the definition of HEV2 is problematic from the topologies of the trees. The major problem is here that only one complete genome sequence and only very few partial genome sequences are available for genotype 2 strains. It is evident from the above mentioned studies that the growing number of HEV and HEV-related sequences calls for a re-consideration of the current taxonomic scheme within the family Hepeviridae. At the level of genera, distinguishing criteria may include host specificity, genome structure as well as phylogenetic data. Based on those criteria, the hepeviruses infecting humans, pigs/wild boars and rabbits might form one genus, because evidence of transmission between theses animals and humans as well as a close phylogenetic relationship of these viruses exist. Another genus may be formed for the hepeviruses infecting rats and the carnivores ferret, mink and fox (putative designation Rocavirus – from rodent and carnivore), mainly because of their phylogenetic relationship, forming a sister group to the Orthohepevirus genus in the phylogenetic tree of the complete genomes (Fig. 5B). In addition, the presence of an additional ORF4, which has been demonstrated in the completely sequenced genomes of rat HEV and ferret HEV, would support this grouping. The hepeviruses of bats, chicken and salmonid fish should each be grouped into a separate genus due to their host association and phylogenetic relationship. The classification of moose HEV is difficult, as it has been detected

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Table 2 Preliminary taxonomical classification scheme of the family Hepeviridae as proposed by the authors. Genus

Virus speciesa

Type species [acc.-No.]

Natural host

Zoonotic potentialb

Disease in human and/or host

Orthohepevirus

Hepatitis E virus 1 Hepatitis E virus 2 Hepatitis E virus 3

Burmese [M80581] Mexican [M74506] Meng [AF082843]

None None Confirmed

Hepatitis E virus 4

T1 [AJ272108]

Man Man Man, pig, wild boar, deer, mongoose, rabbit, rat (?) Man, pig wild boar, cattle (?) and sheep (?)

Hepatitis E virus 5c

JBOAR135-Shiz09 [AB573435]

Wild boar

n.a.

Hepatitis E Hepatitis E Hepatitis E/subclinical in swine Hepatitis E/subclinical in swine Unknown

Rat hepatitis E virusc Ferret hepatitis E virus Mink hepatitis E virus (putative) Fox hepatitis E virus (putative)

R63 [GU345042] FRHEV20 [JN998607] 1119-3 [KC802090]d

Different rat species, shrew (?) Ferret Mink

None n.a. n.a.

Subclinical Unknown Unknown

Fox3 [KC692370]d

Red fox

n.a.

Unknown

Chiropteranhepevirus

Bat hepatitis E virusc

BS7 [JQ001749]

Bat (Hipposideridae, Phyllostomidae, Vespertilionidae)

n.a.

Unknown

Avihepevirus

Avian Avian Avian Avian

06-561 [AM943647] USA [AY535004] 05-5492 [AM943646] TWNaHEV [KF511797]

Chicken Chicken Chicken Chicken

None None None None

BLSD/HSS/subclinical BLSD/HSS/subclinical BLSD/HSS/subclinical BLSD/HSS/subclinical

Piscihepevirus

Cutthroat trout virus

Heenan 88 [NC_015521]

Cutthroat trout

n.a.

None

Not assigned

Moose hepatitis E virus (putative)

AlgSwe2012 [KF951328]d

Moose

n.a.

Unknown

Rocahepevirus

hepatitis hepatitis hepatitis hepatitis

E E E E

virus virus virus virus

1 2 3 4

Confirmed

(?) Mammal species where HEV-related sequences have been reported only in one publication, probably reflecting rather a spillover infection of a non-reservoir species than an infection of a reservoir. n.a., not analyzed. BLSD, big liver and spleen disease. HSS, hepatitis-splenomegaly syndrome. a Suggestions for definition of distinct virus species are preliminary and should be revised after the availability of reliable cut-off values for the percentage of genome sequence similarity. b Experimentally determined (see Fig. 4). c Genetic heterogenicity within this virus species may suggest the subdivision into more species. d Only partial sequences are available.

in only one animal until now and the genome sequence is so far incomplete. Further grouping of hepeviruses at the species level has to be discussed. According to ICTV, a virus species is ‘‘a polythetic class of viruses that constitutes a replicating lineage and occupies a particular ecological niche’’ (King et al., 2012). Given the fact that HEV genotype 1 strains exclusively replicate in humans, whereas genotype 3 strains infect humans, pigs, wild boars and other animal species, the ecological niche of these genotypes is obviously not the same. Therefore, the current taxonomic grouping of these genotypes into the same virus species hepatitis E virus seems to be not appropriate and the scheme should be changed. However, the host specificity of a specific strain is often difficult to determine. Therefore, phylogenetic data, which reflect the degree of independent evolution of virus strains (and therefore may indicate the ‘‘replicating lineages’’), may be used for classification. Sequence similarity plots have been widely used for definition of sequence similarity cut-offs for virus species in other virus families (Matthijnssens et al., 2012; de Villiers et al., 2004; Maes et al., 2009) and should be developed for the family Hepeviridae in future. Drexler et al. (2012) used a similar approach based on deduced amino acid sequences of ORF1- and ORF2-derived proteins to substantiate the taxonomic grouping into human HEV-like, rodent, avian and bat hepeviruses, which might be adapted for definition of virus species. Virus species based on only one detected virus should be only tentatively grouped. The definition of subtypes seems to be not supported by sequence analyses of the broad variety of newly described strains (Smith et al., 2013). A suggested taxonomic scheme for the family Hepeviridae as proposed by the

authors, which is based on the designations developed by Meng (2013), but changed according to the above mentioned criteria, is presented in Table 2. The included suggestions for creation of distinct virus species, substituting genotype classifications, are preliminary and should be revised after the availability of reliable cut-off values for the percentage of genome sequence similarity.

8. Conclusions and perspectives Due to the application of novel detection methods, the family Hepeviridae is rapidly expanding in recent years. The identification of many novel HEV-like viruses in divergent hosts revealed an unexpected heterogeneity within this virus family. However, most of the newly detected viruses have been only poorly characterized so far and the knowledge about their geographical distribution as well as their host specificity is very limited. Thus, the zoonotic potential of most of the novel viruses remains to be determined and efforts should be taken to assess the risk of human infections with these viruses. Besides their potential role as zoonotic agents, the novel vertebrate hepeviruses may be candidates as useful surrogates for human HEV strains. As reproducible animal models for human HEV infections are so far based on sophisticated but expensive infection experiments with larger mammals like monkeys and pigs, the development of rodent or small carnivore models using rat, ferret or mink HEV should be considered. In addition, propagation of human HEV strains in cell culture has still a low efficiency. In contrast, the fish hepevirus CTV has been shown to replicate

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highly efficiently in cell cultures. Trials to isolate and propagate the other novel hepeviruses from the distinct animal species should be encouraged. The development and testing of reservoir animalderived cell lines, e.g. from bats, rodents or shrews, has been described recently (Eckerle et al., 2014a,b). Another aspect of interest on the novel hepeviruses is their possible involvement in diseases of animals. This may be of special importance for hepeviruses infecting economically important animal species. Interestingly, there are only very limited detailed studies available focusing on the clinical relevance of the infection for the longer-known avian HEV. This may be attributed to the fact that in numerous cases the infection is subclinical and the conditions to induce BLSD or HSS are largely unknown. The lack of a cultivation system for avian HEV hinders more detailed in vitro and in vivo studies, although infectious cDNA clones available recently may compensate some of the deficiencies. It can be expected that novel hepeviruses will be detected in other animal species in the near future. Serological evidence for infections of other animal species with HEV-like viruses already exists, which includes food-producing domestic animals like cattle and goat (Dong et al., 2011; Sanford et al., 2013). However, in order to reconstruct the phylogenetic history of the hepeviruses, the analysis of samples from distantly related animal taxa like reptiles as recently performed for other virus families (e.g. arenaviruses: Hetzel et al., 2013; paramyxoviruses: see Hyndman et al., 2013), may also be useful. Taxonomic classification would need additional efforts which should include phylogenetic analyses of complete genomes of sufficient numbers and geographical origins of hepeviruses and definition of solid criteria and distinct thresholds for taxa definition (Johne et al., 2011) as well as investigations of the host specificity. The assessment of the expanding genetic diversity within the family Hepeviridae will widen up our understanding on the evolution, host range, pathogenicity and transmission pathways of a group of interesting and clinical significant viruses. Acknowledgements The investigations in the laboratory of Rainer G. Ulrich were supported by the German Center for Infection Research (DZIF) and those in the laboratory of Reimar Johne by a grant of the German Federal Ministry of Education and Research (BMBF) executed within the framework of the project ZooGloW (FKZ 13N12697). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.meegid.2014.06. 024. References Agunos, A.C., Yoo, D., Youssef, S.A., Ran, D., Binnington, B., Hunter, D.B., 2006. Avian hepatitis E virus in an outbreak of hepatitis-splenomegaly syndrome and fatty liver haemorrhage syndrome in two flaxseed-fed layer flocks in Ontario. Avian Pathol. 35, 404–412. Andraud, M., Dumarest, M., Cariolet, R., Aylaj, B., Barnaud, E., Eono, F., Pavio, N., Rose, N., 2013. Direct contact and environmental contaminations are responsible for HEV transmission in pigs. Vet. Res. 28 (44), 102. Arankalle, V.A., Chobe, L.P., Chadha, M.S., 2006. Type-IV Indian swine HEV infects rhesus monkeys. J. Viral Hepat. 13 (11), 742–745. Arankalle, V.A., Joshi, M.V., Kulkarni, A.M., Gandhe, S.S., Chobe, L.P., Rautmare, S.S., Mishra, A.C., Padbidri, V.S., 2001. Prevalence of anti-hepatitis E virus antibodies in different Indian animal species. J. Viral Hepat. 8 (3), 223–227. Aye, T.T., Uchida, T., Ma, X.Z., Lida, F., Shikata, T., Zhuang, H., Win, K.M., 1992. Complete nucleotide sequence of a hepatitis E virus isolated from the Xinjiang epidemic (1986–1988) of China. Nucleic Acids Res. 20 (13), 3512. Baechlein, C., Schielke, A., Johne, R., Ulrich, R.G., Baumgaertner, W., Grummer, B., 2010. Prevalence of hepatitis E virus-specific antibodies in sera of German domestic pigs estimated by using different assays. Vet. Microbiol. 144, 187–191.

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