Host receptor networking and molecular mechanisms of innate immune evasion in hepatitis E virus pathogenesis
6 affiliations
- 1Infectious Disease Research Department, King Abdullah International Medical Research Center
- 2King Saud bin Abdulaziz University for Health Sciences
- 3Ministry of the National Guard - Health Affairs
- 4Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne
- 5State Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences
- 6Hunan Provincial Key Laboratory of Medical Virology, Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology, Hunan University
Abstract
Hepatitis E virus (HEV), the causative agent of hepatitis E, is a major global health concern, with seroprevalence estimates suggesting that approximately 939 million people worldwide have been exposed to the virus. Although historically regarded as a predominantly self-limiting cause of acute hepatitis, HEV is now recognized as a clinically diverse pathogen capable of causing acute liver failure, chronic hepatitis in immunocompromised individuals, and neurological, renal, hematological, and other extrahepatic manifestations. This review integrates current understanding of HEV cell entry, tissue and host tropism, innate immune recognition, and viral immune evasion. HEV exists in two particle forms: non-enveloped (nHEV) and quasi-enveloped (eHEV). Both use distinct but partially convergent entry pathways involving attachment factors, entry cofactors, endosomal trafficking machinery, and lysosomal processing rather than a single canonical receptor. We evaluate the evidence supporting established and candidate host factors and propose a dual-module heuristic to organize current receptor evidence while emphasizing that this framework remains provisional and requires validation in physiologically relevant models. We further examine how viral genetic determinants, receptor engagement, post-entry replication compatibility, and host antiviral responses collectively shape tissue tropism and cross-species transmission. Innate recognition involves RIG-I and MDA5 signaling through MAVS–TBK1–IRF3, alongside TLR pathways converging on IRF3 and NF-κB, driving type I and III interferon responses. HEV, however, counteracts these defenses at multiple levels. Functional regions within ORF1 interfere with pathogen sensing and interferon signaling; ORF2 contributes to immune evasion through a secreted glycosylated decoy isoform and modulation of NF-κB signaling; and ORF3 exerts context-dependent immunomodulatory effects while facilitating quasi-enveloped virion egress through the ESCRT pathway. Together, these mechanisms support a model in which HEV induces a sustained but incompletely effective antiviral response that may permit viral persistence, particularly under immunosuppression. Integrating entry biology with tropism, zoonotic determinants, and innate immune evasion highlights key unresolved mechanisms and provides a framework for developing improved experimental models, antiviral strategies, and diagnostic approaches for hepatitis E.
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BibTeX
@article{zohaib2026host,
title = {{Host receptor networking and molecular mechanisms of innate immune evasion in hepatitis E virus pathogenesis}},
author = {Ali Zohaib and Maham Yamin and Muhammad Usama Butt and Xing-Yi Ge and Safia S. Aljedani and Rwaa Hussin Abdulal},
journal = {Frontiers in Microbiology},
year = {2026},
month = oct,
doi = {10.3389/fmicb.2026.1938537},
url = {https://www.frontiersin.org/articles/10.3389/fmicb.2026.1938537/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Host receptor networking and molecular mechanisms of innate immune evasion in hepatitis E virus pathogenesis
AU - Ali Zohaib
AU - Maham Yamin
AU - Muhammad Usama Butt
AU - Xing-Yi Ge
AU - Safia S. Aljedani
AU - Rwaa Hussin Abdulal
PY - 2026
DA - 2026/10/19
JO - Frontiers in Microbiology
DO - 10.3389/fmicb.2026.1938537
UR - https://www.frontiersin.org/articles/10.3389/fmicb.2026.1938537/full
AB - Hepatitis E virus (HEV), the causative agent of hepatitis E, is a major global health concern, with seroprevalence estimates suggesting that approximately 939 million people worldwide have been exposed to the virus. Although historically regarded as a predominantly self-limiting cause of acute hepatitis, HEV is now recognized as a clinically diverse pathogen capable of causing acute liver failure, chronic hepatitis in immunocompromised individuals, and neurological, renal, hematological, and other extrahepatic manifestations. This review integrates current understanding of HEV cell entry, tissue and host tropism, innate immune recognition, and viral immune evasion. HEV exists in two particle forms: non-enveloped (nHEV) and quasi-enveloped (eHEV). Both use distinct but partially convergent entry pathways involving attachment factors, entry cofactors, endosomal trafficking machinery, and lysosomal processing rather than a single canonical receptor. We evaluate the evidence supporting established and candidate host factors and propose a dual-module heuristic to organize current receptor evidence while emphasizing that this framework remains provisional and requires validation in physiologically relevant models. We further examine how viral genetic determinants, receptor engagement, post-entry replication compatibility, and host antiviral responses collectively shape tissue tropism and cross-species transmission. Innate recognition involves RIG-I and MDA5 signaling through MAVS–TBK1–IRF3, alongside TLR pathways converging on IRF3 and NF-κB, driving type I and III interferon responses. HEV, however, counteracts these defenses at multiple levels. Functional regions within ORF1 interfere with pathogen sensing and interferon signaling; ORF2 contributes to immune evasion through a secreted glycosylated decoy isoform and modulation of NF-κB signaling; and ORF3 exerts context-dependent immunomodulatory effects while facilitating quasi-enveloped virion egress through the ESCRT pathway. Together, these mechanisms support a model in which HEV induces a sustained but incompletely effective antiviral response that may permit viral persistence, particularly under immunosuppression. Integrating entry biology with tropism, zoonotic determinants, and innate immune evasion highlights key unresolved mechanisms and provides a framework for developing improved experimental models, antiviral strategies, and diagnostic approaches for hepatitis E.
SN - 1664-302X
ER -