Existence of human-virus chimeric proteins generated during infection

Influenza A virus (IAV) is a threat to mankind because it generates yearly epidemics and poorly predictable sporadic pandemics with catastrophic potential. Influenza has a small RNA genome (~14 Kb) composed of 8 mini-chromosomes (segments). Segments encode both structural proteins and proteins expressed only during infection. Segments are constituted by a 5'UTR followed by a coding region and a 3'UTR. Transcription of IAV RNA into mRNA depends on host RNA Polymerase II, as the viral polymerase cleaves 5' capped cellular nascent transcripts to be used as primers to initiate mRNA synthesis. We hypothesized that host nascent transcripts bearing AUG could generate upstream ORFs in the viral segments, a phenomenon that would depend on the translatability of the viral 5'UTRs. Using orthogonal datasets we report the existence of this mechanism, which generate host-virus chimeric proteins. We show that most segments encode proteins in this manner, expanding the proteome diversity of IAV in infected cells. Host-virus chimeric proteins are conserved across IAV strains, pointing to an evolutionary conservation of function achieved by sampling of the evolutionary space before gene fixation. Thus, we discover a mechanism that generate human-virus chimeric proteins during infection. Overall design: (1) Examination of 2 PB1-UFO mutants (2) Examination of PB1-UFO signature and the host transcriptome in the lung tissue of mice