Innate Immune Sensing Pathways as Determinants of Viral Pathogenesis

ABSTRACT: Innate immune sensing constitutes the first line of host defense against viral infections and critically shapes subsequent immune responses. Recent advances have redefined this system as a highly specialized and dynamic network capable of discriminating between diverse viral signatures and mounting tailored antiviral programs. Cytosolic and endosomal pattern recognition receptors, including RIG-I-like receptors, cGAS–STING, and Toll-like receptors, detect viral nucleic acids and initiate signaling cascades that culminate in interferon production and inflammatory responses. Emerging evidence highlights that the timing, magnitude, and cellular context of these early sensing events are key determinants of viral pathogenesis. Rapid and coordinated activation of innate pathways promotes viral control, whereas delayed or dysregulated responses can result in excessive inflammation and tissue damage. In parallel, viruses have evolved sophisticated strategies to evade or subvert host sensing mechanisms, thereby influencing disease severity and transmission. Furthermore, recent technological advances, particularly in single-cell and systems immunology, have uncovered previously unrecognized layers of complexity in antiviral sensing and response heterogeneity. In this review, we synthesize current knowledge on innate immune sensing pathways and discuss how their regulation dictates the balance between protective immunity and immunopathology. We also highlight emerging therapeutic opportunities targeting these pathways and highlight important areas for future investigation in viral immunology.