Detailed single-cell mapping of the transcriptional response to a virus infection driven by copy-back viral genomes

the antiviral response to several clinically significant viruses, including respiratory syncytial virus and parainfluenza virus, is driven by copy-back viral genomes (cbvgs) generated during virus replication. however, the broader impact of cbvgs on the functional states of host cells remains undefined. here, we developed a single-cell rna-sequencing and computational framework to map cbvg-driven host responses during sendai virus infection. unsupervised profiling identified distinct transcriptional states throughout the course of infection, highlighting a shift from early antiviral signaling to later inflammatory and remodeling programs. stratifying infected cells by cbvg status demonstrated that cbvg-positive cells initiate interferon and chemokine programs, which later spread to cbvg-negative cells. at later stages, cbvg-positive cells acquire additional signaling, cytoskeletal, transcriptional, and stress-adaptation programs, which are absent in cbvg-clean infection. this work defines the broader cbvg-driven layered and dynamic host response and provides a valuable high-resolution resource of the temporal cellular response to a virus infection.