Quantitative Proteomics Identifies Host Factors Modulated during Acute Hepatitis E Virus Infection in the Swine Model

Abstract

Hepatitis E virus (HEV) causes acute enterically transmitted hepatitis. In industrialized countries, it is a zoonotic disease, with swine being the major reservoir of human HEV contamination. The occurrence and severity of the disease are variable, with clinical symptoms ranging from asymptomatic to self-limiting acute hepatitis, chronic infection, or fulminant hepatitis. In the absence of a robust cell culture system or small-animal models, the HEV life cycle and pathological process remain unclear. To characterize HEV pathogenesis and virulence mechanisms, a quantitative proteomic analysis was carried out to identify cellular factors and pathways modulated during acute infection of swine. Three groups of pigs were inoculated with three different strains of swine HEV to evaluate the possible role of viral determinants in pathogenesis. Liver samples were analyzed by a differential proteomic approach, two-dimensional difference in gel electrophoresis, and 61 modulated proteins were identified by mass spectroscopy. The results obtained show that the three HEV strains replicate similarly in swine and that they modulate several cellular pathways, suggesting that HEV impairs several cellular processes, which can account for the various types of disease expression. Several proteins, such as heterogeneous nuclear ribonucleoprotein K, apolipoprotein E, and prohibitin, known to be involved in other viral life cycles, were upregulated in HEV-infected livers. Some differences were observed between the three strains, suggesting that HEV's genetic variability may induce variations in pathogenesis. This comparative analysis of the liver proteome modulated during infection with three different strains of HEV genotype 3 provides an important basis for further investigations on the factors involved in HEV replication and the mechanism of HEV pathogenesis. IMPORTANCEHepatitis E virus (HEV) is responsible for acute hepatitis, with clinical symptoms ranging from asymptomatic to self-limiting acute hepatitis, chronic infection, or fulminant hepatitis. In industrialized countries, HEV is considered an emerging zoonotic disease, with swine being the principal reservoir for human contamination. The viral and cellular factors involved in the replication and/or pathogenesis of HEV are still not fully known. Here we report that several cellular pathways involved in cholesterol and lipid metabolism or cell survival were modulated during HEV infection in the swine model. Moreover, we observed a difference between the different swine strains, suggesting that HEV's genetic variability could play a role in pathogenesis. We also identified some proteins known to be involved in other viral cycles. Our study provides insight into the mechanisms modulated during HEV infection and constitutes a useful reference for future work on HEV pathogenesis and virulence.H epatitis E virus (HEV) is responsible for major epidemics of acute hepatitis in low-and middle-income countries worldwide. In industrialized countries, it is an emerging problem, as...

Proteomic Comparative Analysis of Pregnancy Serum Facilitating Hepatitis E Virus Replication in Hepatoma Cells

“…The other proteins were implicated in phagosome, calcium signaling pathway, transcriptional regulation, natural killer cell-mediated cytotoxicity, B-cell receptor signaling pathway, complement and coagulation cascades, and cytoskeleton regulation. The result was similar to that reported in acute HEV infection in a swine model with regulated proteins mainly involved in metabolism, toxicity/inflammatory response, and cytoskeleton trafficking (Rogee et al, 2015). Clusters of orthologous group functional classification is mainly involved in post-translational modification, protein turnover, chaperones, translation, ribosomal structure and biogenesis, energy production and conversion, and cytoskeleton.…”

“…Moreover, Rogee et al (Rogee et al, 2015) identified 61 modulated proteins (Apo E and prohibiting) in the HEV-infected liver of swine; these proteins are known to be involved in other viral life cycles. In the present study, Apo E was also identified in HEV-infected HepG2 cells, indicating that Apo E may be important in HEV infection.…”

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