Specific Plasma MicroRNA Signatures Underlying the Clinical Outcomes of Hepatitis E Virus Infection

Abstract

The pathogenic mechanisms determining the diverse clinical outcomes of HEV infection (e.g., self-limiting vs chronic or symptomatic vs asymptomatic) are not yet understood. Because specific microRNA signatures during viral infection inform the cellular processes involved in virus replication and pathogenesis, we investigated plasma microRNA profiles in 44 subjects, including patients with symptomatic acute (AHE, n = 7) and chronic (CHE, n = 6) hepatitis E, blood donors with asymptomatic infection (HEV BDs, n = 9), and anti-HEV IgG+IgM- (exposed BDs, n = 10) and anti-HEV IgG-IgM- (naïve BDs, n = 12) healthy blood donors. By measuring the abundance of 179 microRNAs in AHE and naïve BDs by RT-qPCR, we identified 51 potencial HEV-regulated microRNAs (PBH < 0.05). Further analysis showed that HEV genotype 3 infection is associated with miR-122, miR-194, miR-885, and miR-30a upregulation and miR-221, miR-223, and miR-27a downregulation. AHE showed significantly higher levels of miR-122 and miR-194, and lower levels of miR-221, miR-27a, and miR-335 compared to HEV BDs. This specific microRNA signature in AHE could promote virus replication and reduce antiviral immune responses, contributing to the development of clinical symptoms. We found that mir-194, miR-335, and miR-221 can discriminate between asymptomatic HEV infections and those developing acute symptoms, whereas miR-335 correctly classify AHE and CHE. Conclusions: Our data suggest that diverse outcomes of HEV infection result from different HEV-induced microRNA dysregulations. The specific microRNA signatures described offer novel information that may serve to develop biomarkers of HEV infection outcomes and improve our understanding of HEV pathogenesis, which may facilitate the identification of antiviral targets.