Hepatitis E virus: host tropism and zoonotic infection

Abstract

Hepatitis E virus (HEV), the causative agent of hepatitis E, is an understudied but important pathogen. HEV typically causes self-limiting acute viral hepatitis, however chronic infection with neurological and other extrahepatic manifestations has increasingly become a significant clinical problem. The discovery of swine HEV from pigs and demonstration of its zoonotic potential led to the genetic identification of very diverse HEV strains from more than a dozen other animal species. HEV strains from pig, rabbit, deer, camel, and rat have been shown to cross species barriers and infect humans. Zoonotic HEV infections through consumption of raw or undercooked animal meat or direct contact with infected animals have been reported. The discovery of a large number of animal HEV variants does provide an opportunity to develop useful animal models for HEV. In this mini-review, we discuss recent advances in HEV host range, and cross-species and zoonotic transmission.

Fig. 1.

A schematic diagram of comparative genomic organization of human, avian, rat, bat, and fish hepatitis E virus (HEV). The genome scale is in bases as shown on the top. The three known open reading frames (ORFs) 1, 2, 3, a putative ORF in genotype 1 HEV, and a putative ORF in rat HEV are represented in different colors: orange, red, green, yellow, and purple, respectively. The putative functional domains within ORF1 are depicted in blue: MT, methytransferase; Y, Y domain; PCP, papain-like cysteine protease; HVR, hypervariable region or PPR, poly-proline region; X, macro domain; Hel, helicase; RdRp, RNA-dependent RNA polymerase. Genbank accession numbers of representative HEV strains were: human genotype 1 HEV (L08816); avian HEV (AY535004); rat HEV (GU345042); bat HEV (JQ001749); fish HEV (HQ731075).

Fig. 2.

A Maximum-likelihood phylogenic tree based on the complete genomes of representatives of the Hepeviridae family. Virus designations include genotype, GenBank accession number, and host. Classification of species is shown on the right according to the International Committee on Taxonomy of Viruses (ICTV) consensus proposal. Complete genome sequences were aligned using the MAFFT algorithm in Geneious Prime software version 2020.1.1. Evolutionary analyses were conducted in Molecular Evolutionary Genetics Analysis software version X (MEGA X) with 1,000 bootstrap replicates. General Time Reversible (GTR) + Gamma Distributed (G) nucleotide substitution model with the lowest Bayesian Information Criterion (BIC) score was selected based on Find Best-Fit Substitution Model (ML) in MEGA X. Filled circles at nodes indicate bootstrap supports of 100%. The tree is drawn to scale, with branch lengths measured in the number of substitutions per site.

Fig. 3.

Global distribution of the four Orthohepevirus species A–D within the genus Orthohepevirus. Countries with either serological and/or molecular evidence of HEV and HEV-related viruses are highlighted. Distribution of the most prevalent HEV genotypes in certain nations or regions were indicated for Orthohepevirus A. A world map was created by using an open source geographic information system Quantum Geographic Information System version 3.10 (http://qgis.osgeo.org) and vector and raster map data from Natural Earth (http://www.naturalearthdata.com).

Fig. 4.

Maximum-likelihood phylogenic trees based on the complete genomes of zoonotic genotypes 3 and 4 HEV representatives. Virus designations include GenBank accession number and host. Complete genome sequences were aligned using the MAFFT algorithm in Geneious Prime software version 2020.1. Evolutionary analyses were conducted in Molecular Evolutionary Genetics Analysis software version X (MEGA X) with 1,000 bootstrap replicates. General Time Reversible (GTR) + Gamma Distributed (G) + Invariable Sites (I) nucleotide substitution model with the lowest Bayesian Information Criterion (BIC) score was selected based on Find Best-Fit Substitution Model (ML) in MEGA X. Filled circles at nodes indicate bootstrap supports of 100%. The scale bar indicates genetic distance. The genotype 1 HEV reference Burma strain (GenBank accession no. M73218) were served as an outgroup of both trees.