MDA5 guards against infection by surveying cellular RNA homeostasis

The preprint operates within the dominant paradigm of immunology, specifically the framework of innate immune sensing of viral infections via pattern recognition receptors (PRRs).

This research refines the current understanding of MDA5 activation. The prevailing model suggests that MDA5, a PRR, is activated by long viral dsRNA. However, this preprint provides evidence that MDA5 primarily binds to host-derived RNA during viral infection, particularly intronic RNA located near Alu elements. It also shows that perturbations in RNA processing, like those caused by viral infection, lead to the accumulation of intronic RNA in the cytoplasm, which in turn activates MDA5. Therefore, while working within the existing paradigm, this preprint proposes a modification to the current model of MDA5 activation. Specifically, it suggests that MDA5 acts as a "guard" of cellular RNA homeostasis, detecting disruptions caused by viral infections, rather than directly sensing viral RNA itself. This refined understanding represents an advancement within normal science, clarifying a specific mechanism within the accepted paradigm. There is no evidence presented to suggest a model drift, crisis or revolution, as the core tenets of innate immunity and PRR function are not challenged. Instead, this research provides a deeper understanding of MDA5’s role within the existing framework.