Various HEV genotypes exhibit different modes of transmission, non-human reservoirs, and abilities of interspecies transmission, although HEV is mainly transmitted in water and food. G3 and G4 are known as causative agents of zoonotic diseases; thus researchers have been prompted to determine the reason that G3 and G4 can cross species barriers, but G1 and G2 strains cannot . G3 HEV is mainly prevalent in humans of certain industrialized nations and has also been isolated from domestic and wild swine, deer, mongoose, rats, and rabbits. Whereas, G4 HEV is associated with sporadic cases of hepatitis E in humans and infects both wild and domestic swine; G4 HEV is also reportedly detected in cattle and sheep [3, 7]. Previous studies have suggested that the zoonotic transmission of HEV across several species, such as humans, pigs, boars, deer, chickens, and rabbits, may be the major mode of infection in non-endemic areas. Contact with swine is the most widely recognized route of occupational exposure to HEV, and humans have been considered as a major source of HEV in endemic areas [8, 9]. Epidemiological patterns also differ significantly between regions where this disease is highly endemic. A recent study in China even found that the seasonal changes in the prevalence of HEV in swine may be attributed to the geographical distribution of different subtypes .
Studies have been conducted regarding HEV transmission in non-human primates such as cynomolgus, rhesus, owl monkeys, and chimpanzees, as well as in pigs, rabbits, and Mongolian gerbils . Experimental HEV infections in animal models have provided relevant information regarding the biological characteristics and pathogenesis of HEV; these animal models are also essential tools used in vaccine and drug test . However, effective tissue culture replication systems of HEV have rarely been developed . Furthermore, the pathogenesis of liver pathology and the replication cycle of HEV remain poorly understood because cultured cells are unable to propagate efficiently in vitro.
G4 is responsible for the majority of sporadic hepatitis E cases affecting humans in China, and the high prevalence of G4 in pig population exacerbates this situation. G4-induced disease symptoms are possibly more severe than other types. In a previous study involving putative HEV G4 virulence determinants, one potential determinant is located in each of the 5ʹ-UTR and 3ʹ-UTR, 3 and 12 determinants are detected in ORF1 and ORF2, respectively, and two determinants are found in the junction . Thus far, at least nine subtypes (4a–4i) of G4 HEV isolates have been identified; numerous new subgenotypes have been reported in humans and pigs [15–18]. In one of our previous surveys, at least four subgenotypes (4c, 4d, 4b, and a new subgenotype) are prevalent in Yunnan Province. Five of the nine known subgenotypes of G4 have been identified as prevalent in Yunnan Province. Furthermore, subtype 4 h is dominant and has been isolated from a human patient with liver failure in south of China .
The lack of a standardized assay for clinical diagnosis remains a challenging issue, thus HEV has been considered as an underreported pathogen of acute hepatitis cases. The diagnosis of HEV infection should depend on RT-PCR and serology. The majority of HEV RT-PCR assays used for diagnosis have been developed by choosing different conserved HEV genomic regions as a target for amplification and primers and probes should also be designed to guarantee the development of highly sensitive and broadly reactive assays because of the wide genetic heterogeneity of the HEV genome . In general, G4 exhibits the lowest nucleotide sequence identity with G2 but higher nucleotide sequence identity in the same genotype. At present, HEV infections are serologically diagnosed by ELISA. The recombinant human HEV capsid antigen undergoes cross-reaction with antibodies to swine HEV in ELISA and has been widely used to detect anti-HEV antibody in swine .
A majority of infections in animals are asymptomatic and have not caused any economic loss in pig farms. As a result, the high prevalence of HEV in swine population cannot attract active management from farmers or authorities. Previous study results indicated that sustained transmission could induce changes in virulence; as such, severe consequences may occur . Meanwhile, the number of published HEV sequences has increased significantly, analysis of genomic sequences of multiple HEV isolates have revealed extensive genomic diversity. Since the development of the first vaccine to prevent hepatitis E infection of humans registered in China in 2011, an effective method to control hepatitis E has been established. Nevertheless, HEV infection should also be controlled in reservoir animals, particularly in swine. Further studies should also be conducted to determine the duration of protection from vaccination, zoonotic transfer mode, difference in virulence between genotype and subgenotype, and vaccine for host animals.