Journal of Hepatology
Volume 33, Issue 5 , Pages 842-845, November 2000

Novel strains of hepatitis E virus identified from humans and other animal species: is hepatitis E a zoonosis?

  • Xiang-Jin Meng

      Affiliations

    • Corresponding Author InformationXiang-Jin Meng, Department of Biomedical Sciences and Pathobiology, Center for Molecular Medicine and Infectious Diseases, Virginia Polytechnic Institute and State University, 1410 Piice's Fork Road, Blacksburg, VA 24061–0342, USA Tel 540 231 6912 Fax 540 231 3426

Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology Virginia Polytechnic Institute and State University Blacksburg Virginia USA

Article Outline

 

Hepatitis E virus (HEV), the causative agent of hepatitis E, is a single positive-stranded RNA virus without an envelope 1., 2.. HEV was classified in the family Caliciviridae, but the lack of common features between HEV and caliciviruses has led to the recent removal of HEV from the family 3., 4.. Hepatitis E is an important public health disease in many developing countries, and the characteristic of HEV infection in these countries is water-borne epidemics 1., 2.. In industrialized countries, where hepatitis E was thought to be non-endemic, anti-HEV antibodies have also been detected in the general populations 1., 2., 5., 6., 7., 8.. The existence of a population of individuals in industrialized countries who are positive for anti-HEV has led to a hypothesis that an animal reservoir(s) for HEV may exist 2., 5.. The recent discovery of swine hepatitis E virus from a pig in USA and its close genetic relatedness with human strains of HEV identified from USA patients 9., 10. lend further credence to such a hypothesis.

In this issue of Journal of Hepatology, Pina et al (11) report the genetic identification of novel HEV strains from sera of hepatitis patients and sewage samples of animal origin from a slaughterhouse in Spain. The two Spanish strains of human HEV (VH1 and VH2) identified shared 93 4% nucleotide sequence identity to each other in a 304 bp region of ORF2 and 92 7% identity in a 371 bp region of ORF1 A third strain of HEV (strain E11) was also identified in animal sewage samples collected from a slaughterhouse that processed about 5000 pigs, 500 sheep and 90 calves per week Since the sewage from human origin in the slaughter-house is distributed separately from that of animal origin (11), it is likely that the E11 strain of HEV is of animal origin Interestingly, the E11 strain is genetically distinct from most known HEV strains worldwide, but is most closely related to the Spanish VH1 and VH2 strains of human HEV 92 1% to 94% nucleotide sequence identities in the ORF2 region. The E11 strain of HEV is more closely related to the US swine HEV and two US strains of human HEV (82 8–85 5% nucleotide sequence identities in the ORF2 region) than to other HEV strains worldwide (71 4–75% identities in the same region). Although the source of strain E11 is not known, it may be of swine origin as the slaughterhouse primarily processed pigs, and pigs in the Barcelona area are found positive for anti-HEV. (11). This interesting study by Pina et al. (11) provided important complementary data to support a current working hypothesis that hepatitis E is a zoonosis.

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Animal Strains of HEV: Serological Evidence and Genetic Identification 

It has been reported that anti-HEV was detected in pigs from developing countries such as Nepal (12), China (13) and Thailand (13) and from industrialized countries such as USA (9), Canada (13), Korea (13) Taiwan 14., 15. and Australia (16) Pina et al (11) also found that about 25% of pigs from Spanish herds are positive for anti-HEV, suggesting that HEV is also enzootic in pigs in Spain In addition to pigs, Kabrane-Lazizi et al (17) found that about 77% of the rats from Maryland, 90% from Hawaii and 44% from Louisiana are also positive for IgG anti-HEV More recently, Favorov et al. (18) also reported the detection of IgG anti-HEV among rodents in USA. In Vietnam where HEV is endemic, anti-HEV was detected in 44% of chickens, 36% of pigs, 27% of dogs and 9% of rats. (19). A recent study by Favorov et al. (20) showed that about 29 to 62% of cows from Somalia, Tajikistan and Turkmenistan (HEV endemic regions), about 42 to 67% of the sheep and goats from. Turkmenistan and about 12% of cows from Ukraine (a non-endemic region) are positive for anti-HEV These serological data strongly suggest that these animal species have been exposed to HEV (or a related agent) and that animal strains of HEV exist However, until recently the source of seropositivities in these animals could not be definitively identified.

In 1997, a novel strain of HEV (designated as swine HEV) was genetically identified and characterized from a pig in USA (9). The genomic organization of swine HEV is very similar to that of human strains of HEV. The USA strain of swine HEV is distinct from other strains of HEV worldwide but is closely related to two USA strains of human HEV (10). More recently, Hsieh et al. (14) reported the identification of a second strain of swine HEV from a pig in Taiwan. This Taiwanese strain of swine HEV shared 97 3% nucleotide sequence identity with a human strain of HEV identified from a retired Taiwanese farmer, but is genetically distinct from the USA. strain of swine HEV More recently, Wu et al. (15) identified yet another novel strain of swine HEV also from pigs in Taiwan Sequence analyses revealed that the swine and human strains of HEV in Taiwan shared 84 to 95%, nucleotide sequence identity but displayed only 72 to 79% nucleotide sequence identity with other known strains of HEV worldwide. In addition to pigs, a variant strain of HEV was reportedly identified from tissue and fecal samples of wild-trapped rodents from Kathmandu Valley, Nepal. (21) Sequence analyses indicated that the HEV sequence recovered from rodents is most closely related to the HEV isolates from patients in Nepal More recently, Payne et al. (22). reported the identification of a virus associated with big liver and spleen disease (BLS) of chickens in Australia Based on the very limited sequence information available, the BLS virus shared about 62% nucleotide sequence identity with human HEV. Genetic identification of HEV strains from swine and rodents and their close genetic relatedness with human strains of HEV, in the same geographic area further strengthens the argument that an animal reservoir(s) for HEV does exist. The article by Pina et al. (11) provides further evidence that genetically distinct animal strains of HEV are geographically clustered with human strains of HEV, suggesting the possibility of zoonotic HEV infections.

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Novel Strains of Human HEV: Where do. They Come From 

Over the last couple of years, numerous genetically distinct strains of HEV have been identified from patients with acute hepatitis in both developing and industrialized countries. In USA, two cases of acute hepatitis E have been reported 23., 24.. The two USA isolates of HEV (US-1 and US-2) are genetically distinct from other known strains of HEV worldwide (about 80% amino acid sequence identity in ORF1) but are closely related to each other and to the USA strain of swine HEV (about 98% amino acid sequence identity in ORF 1). Similarly, several novel isolates of HEV have been identified from patients in Taiwan with no history of travel to endemic regions. 14., 15., 25.. These Taiwanese isolates are genetically distinct from other known strains of HEV but are closely related to strains of swine HEV identified from pigs in Taiwan Pina et al. (11) found that the Spanish E11 strain of HEV of possible swine origin is closely related to the VH1 and VH2. Spanish strains of human HEV, but is less related to other known strains of HEV. Taken together, these data provide compelling evidence that swine HEV infects and causes hepatitis in humans.

Recently, several other novel strains of HEV have also been identified from patients in both HEV endemic and non-endemic regions A novel Italian strain of human HEV was found to share only about 79 5 to 85 8% nucleotide sequence identity with other known strains of HEV (26). Schlauder et al. (27) recently identified another. Italian and two Greek novel strains of HEV The sequences of the Greek and Italian strains of HEV differed significantly from other known strains of HEV and from each other, and the two Greek strains also varied extensively in their sequences. In endemic regions, novel strains of HEV distinct from the known epidemic strains have also been identified Wang et al. (28) found that a novel. Chinese strain of human HEV (T1) is related to the Taiwanese swine and human HEV strains reported by Hsieh et al. (14). Van Cuyck-Gandre et al. (29) reported two phylogenetically distinct strains of HEV recovered only 1 year apart from two outbreaks in Pakistan Wang et al. (30) identified six novel isolates of HEV from Chinese patients negative for anti-HEV. These six novel Chinese isolates of HEV are genetically similar to each other but differ extensively from other known HEV strains and form a distinct genotype Huang et al (31) have also identified two unique strains of HEV (G-20 and G-9) from patients in China they shared about 89% sequence identity with each other but only 76–78% identity with other known strains of HEV including other Chinese strains. In Nigeria, a genetically distinct strain of HEV has also been identified from native Nigerians with acute hepatitis (32).

The intriguing fact about these recently identified novel strains of human HEV is that they are genetically distinct from each other and from other known strains of HEV Although the source of these novel HEV strains is not clear, it is plausible that they may be of animal origins since several potential animal reservoirs for HEV exist If this is true, then the question becomes why do they differ extensively in their sequences and why do they cause sporadic cases of acute hepatitis E A speculative scenario is that some domestic or farm animals may have their own genetically distinct strains of HEV that are enzootic in their respective animal species within the same geographic area Occasionally, these animal strains of HEV may infect humans through direct contact with infected animals. These enzootic animal strains cause sporadic cases of acute hepatitis E in humans since they are not well adapted to replication in humans as compared to the endemic or epidemic strains. If the above scenario is true, then the geographic locations and the animal species from which the virus originated will likely determine the genetic make-up of a particular strain of HEV recovered from sporadic cases of acute hepatitis E. It will be important to determine whether there are fundamental differences in host range or pathogenicity among endemic or epidemic strains of HEV circulating in humans as compared to animal strains that are mainly enzoonotic in their respective animal species.

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Cross-species Infection of HEV: Is Hepatitis E a Zoonosis 

It has been shown that swine HEV can cross species barriers and infect non-human primates and conversely, the US-2 strain of human HEV infects specific-pathogen-free (SPF) pigs. (10). The inoculated pigs rapidly became viremic and seroconverted to anti-HEV, suggesting that the US-2 strain is already competent to replicate in swine and may be of swine origin. A Central Asian strain of human HEV reportedly infects Russian domestic swine (33), although Meng et al. (34) were unable to infect SPF swine with two well-characterized epidemic strains of human HEV a Mexican strain and a Pakistani strain It is possible that these epidemic strains may have a more limited host range than does swine HEV or other HEV strains of animal origin Cross-species infection of HEV has also been reported in other animal species Lambs are reportedly infected with human HEV isolates Osh-225 and Osh-228 (35) Similarly, Wistar rats are reportedly infected with a human stool suspension containing infectious HEV (36) However, there is no independent confirmation of these reports It will be interesting to see if the E11 strain of HEV reported by Pina et al. (11) can be transmitted to swine or other animal species.

The potential for cross-species infection by HEV raises an important public health concern Individuals in high-risk groups such as pig handlers may be at risk of zoonotic HEV infection Recently, a limited number of pig handlers from two HEV endemic countries was tested for the prevalence of anti-HEV, and the majority of pig handlers tested were positive (13). In another study, Hsieh et al (14) found that about 26 7% of the Taiwanese pig handlers are positive for anti-HEV compared to only about 8% in control subjects Because of the limited number of pig handlers tested, further studies with a larger number of pig handlers from industrialized countries are warranted Recently, Karetnyi et al (37) found that anti-HEV prevalence in Iowa patients with non-A–C hepatitis (4 9%) and in field workers from the Iowa Department of Natural Resources (5 7%) is significantly higher than that in normal blood donors (2%, p<0 05), suggesting that human populations with occupational exposure to wild animals have increased risks of HEV infection and that other animal species may also involve in HEV transmission.

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Conclusion 

In summary, the article by Pina et al. (11) has provided an impetus for further study of the natural history, epidemiology and pathogenesis of HEV. These recently identified novel strains of HEV may affect HEV vaccine development and diagnosis Although the experimental recombinant HEV vaccines appear to be effective 38., 39., their efficacy must be thoroughly evaluated for protection against these emerging strains of HEV. The current diagnostic assays may not be adequate for the many novel strains of HEV and thus, development of more reliable diagnostic assays for HEV is warranted. The occurrence of acute hepatitis E in industrialized countries may be underestimated, as sporadic cases of acute hepatitis E may go undiagnosed (6). Therefore, clinicians in industrialized countries should consider the possibility of HEV infection in cases of acute non-A, B, C hepatitis.

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Acknowledgements 

The author's current research on HEV is supported by grants from the National Institutes of Health (AI01653-01, AI46505-01) I wish to thank Drs Robert H Purcell and Suzanne U Emerson in the Laboratory of Infectious Diseases at NIAID, NIH, and Dr Patrick G Halbur at Iowa State University for support and collaboration I would also like to thank Drs Thomas E Toth and Gholamreza Haqshenas for critical review of the manuscript, and Mr Denis Guenette for editorial assistance

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PII: S0168-8278(00)80319-0

Journal of Hepatology
Volume 33, Issue 5 , Pages 842-845, November 2000

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