The Role of Host Receptors and Associated Co-Factors in Viral Tropism and Pathogenesis

Viruses exploit cell-surface receptors, co-receptors/attachment factors, and entry-activating proteases to invade cells. Variation in the presence, abundance, and properties of these host factors is a primary determinant of tissue, cell-type, and species range, with downstream consequences for replication routes, immune evasion, transmissibility, and clinical severity. These host features help explain susceptibility and cross-species transmission in domestic and wild animals and highlight opportunities for diagnostics and host-directed intervention within a One Health framework.

Despite rapid progress, important gaps remain. First, integrative maps that connect receptor/co-factor networks to downstream signaling and in vivo pathophysiology remain limited. Also, the contributions of polymorphisms, post-translational modifications (e.g., glycosylation), and inflammatory microenvironments to tissue-specific disease are poorly defined. Finally, comparative evidence across viral families and animal hosts is uneven, limiting generalizable principles of receptor usage and spillover prediction. Finally, translation from mechanism to intervention - diagnostics, decoy receptors, blocking antibodies, small molecules, and other host-directed strategies - requires standardized assays and datasets to enable reproducibility and cross-study synthesis.

We welcome contributions that include, but are not limited to:

• Receptor/co-factor networks, including attachment factors and entry-activating proteases, and their context-dependent usage
• Determinants of tissue, cell-type, and species tropism; host range expansion and spillover risk
• Effects of host genetic variation, glycosylation, and expression dynamics across tissues, development, and inflammation on infection outcomes
• Receptor trafficking, membrane organization, and signaling, and their links to immune evasion and pathogenesis
• Systems-level receptor mapping (CRISPR screens, perturb-seq), single-cell/spatial transcriptomics and proteomics, and glycomics, with in vivo validation
• Comparative analyses across viral families in domestic and wild animal hosts (veterinary and One Health perspectives)
• Translational and diagnostic strategies: receptor-blocking antibodies, decoy receptors, small-molecule entry inhibitors, receptor-informed diagnostics, and host-directed interventions
• Methods, datasets, and standards that improve reproducibility, benchmarking, and cross-study synthesis
• Perspectives and opinions addressing controversies, terminology, and future research priorities

Together, these advances will deepen our understanding of mechanisms, connect basic research to clinical practice, and speed the development of equitable, reproducible strategies to prevent, detect, and mitigate viral threats across species.

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This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

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• FAIR² Data
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• Hypothesis and Theory
• Methods
• Mini Review
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• Original Research
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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: viral tropism, viral-receptor interactions, Virus entry, Viral attachment and fusion, Protease-activated entry, viral pathogenesis, virus host receptors, viral co-factors

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.