Aberrant host mRNA partitioning in Ebola virus condensates driven by RNA folding perpetuates species-dependent interferon response

RNA viruses form membraneless condensates in host cells to drive replication, but whether these compartments also regulate host RNAs remains unclear. Using MERFISH-based subcellular transcriptomics, we quantified cellular mRNA recruitment into Ebola virus condensates under basal and IFN-stimulated states. In the basal state, cellular RNAs with minimally folded coding regions are selectively recruited. Under IFN-stimulation, however, interferon-stimulated genes (ISGs) with structured 3′UTRs concentrate in viral condensates. Both features, minimally-folded coding regions and structured 3′UTRs, are conserved across negative-strand RNA viruses, supporting viral genome retention in condensates. For cellular mRNAs, however, partitioning into condensates escapes XrnI-mediated decay, prolongs RNA-half-life and amplifies ISG expression. This selective stabilization links condensate function to RNA regulation as a molecular determinant of viral and host evolution and disease pathogenesis. Fruit bats, which do not experience severe disease for many negative-strand viruses, instead have ISGs with reduced 3′UTR folding, and may evade condensate-sequestration, enabling balanced antiviral responses.