TriLock-FISH enables in situ discrimination of influenza cRNA and mRNA for single-cell analysis of viral replication and transcription

Influenza A virus produces three RNA species—viral RNA (vRNA), complementary RNA (cRNA), and messenger RNA (mRNA)—whose synthesis and trafficking are spatially compartmentalized. However, the high sequence similarity between cRNA and mRNA hinders their distinction in situ, limiting understanding of the spatial organization of the viral replication-transcription dynamics. Here, triple-lock fluorescence in situ hybridization (TriLock-FISH) was developed to distinguish vRNA, cRNA, and mRNA in situ with high specificity. TriLock-FISH enabled a genome-wide, time-resolved single-cell atlas of RNA abundance and localization, revealing marked cell-to-cell variation in RNA abundance but relatively conserved spatial organization. cRNA was found to be predominantly nuclear, with a small but reproducible cytoplasmic fraction. Application to infected mouse lung tissue demonstrated simultaneous spatial detection of all viral RNA species. This approach provides a highly specific framework for single-cell analysis of RNA virus replication and transcription.