Viral Receptors as Host–Pathogen Control Nodes Linking Entry, Signalling, and System-Level Pathogenesis

Viral receptors have traditionally been viewed as docking sites that mediate viral attachment and entry. However, this perspective no longer captures the full complexity of receptor function during infection. Receptor engagement links viral binding to intracellular trafficking, signal transduction, barrier integrity, and ultimately disease outcome. Rather than acting solely as entry determinants, receptors influence endocytic routing, cellular permissiveness, tissue tropism, immune responses, and systemic dissemination. A functional distinction between attachment factors, entry receptors, co-receptors or accessory factors, and receptor-like immune sensors is essential for accurate mechanistic interpretation and translational applications. This review examines the events that follow receptor engagement, including intracellular routing, signalling, regulation of receptor availability, and host determinants of susceptibility. Particular emphasis is placed on the concept of receptor landscapes, defined as dynamic and spatially organised receptor topologies across epithelial and endothelial barriers that are shaped by development, ageing, inflammation, and comorbidities. In this view, systemic disease is viewed as the consequence of failures in receptor-defined barriers and interconnected feedback circuits across organs. Finally, we discuss the implications of this perspective for host-directed therapies, receptor decoys, and biomarker development. Reframing receptors as regulatory hubs helps explain differences in viral tropism and disease severity and highlights new opportunities for host-targeted intervention.