{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Infectious Disease Research Department, King Abdullah International Medical Research Center",
    "King Saud bin Abdulaziz University for Health Sciences",
    "Ministry of the National Guard - Health Affairs",
    "Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne",
    "State Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences",
    "Hunan Provincial Key Laboratory of Medical Virology, Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology, Hunan University"
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Ali Zohaib"
    },
    {
      "affs": [
        3
      ],
      "name": "Maham Yamin"
    },
    {
      "affs": [
        4
      ],
      "name": "Muhammad Usama Butt"
    },
    {
      "affs": [
        5
      ],
      "name": "Xing-Yi Ge"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Safia S. Aljedani"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Rwaa Hussin Abdulal"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/99st6rc19zzvz.bib",
  "cited_by": 0,
  "doi": "10.3389/fmicb.2026.1938537",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13727105/?tool=EBI",
  "id": "99st6rc19zzvz",
  "issns": [
    "1664-302X"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fmicb.2026.1938537/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Review"
    ],
    [
      "openalex",
      "2721|Hepatitis Viruses Studies and Epidemiology"
    ]
  ],
  "openalex": "W7222971736",
  "pdf_url": "https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2026.1938537/pdf",
  "pmcid": "PMC13727105",
  "pmid": "42974339",
  "published": "2026-10-19",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/99st6rc19zzvz.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:12Z",
      "native_id": "10.3389/fmicb.2026.1938537",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fmicb.2026.1938537/full"
    },
    {
      "first_seen": "2026-11-03T15:20:51Z",
      "native_id": "PMC:PMC13727105",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13727105"
    },
    {
      "first_seen": "2026-11-04T15:20:48Z",
      "native_id": "MED:42974339",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42974339"
    },
    {
      "first_seen": "2026-11-05T12:23:17Z",
      "native_id": "PMC13727105",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fmicb.2026.1938537"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "issn:1664-302X",
      "subfield": "microbiology"
    }
  ],
  "title": "Host receptor networking and molecular mechanisms of innate immune evasion in hepatitis E virus pathogenesis",
  "title_text": "Host receptor networking and molecular mechanisms of innate immune evasion in hepatitis E virus pathogenesis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:22:53Z",
  "url": "https://research.draconitic.com/paper/99st6rc19zzvz",
  "venue": "Frontiers in Microbiology",
  "versions": []
}