Transcriptomic analysis of phage-mammalian cell interaction reveals diverse phage immunobarcodes

The phage-mammalian cell interactome is an emerging research frontier essential for uncovering the diverse impacts phages may have on humans. Here, we investigate the crosstalk of six distinct <i>Acinetobacter baumannii</i> phages with A549 epithelial cells and RAW264.7 macrophages. Our findings indicate that phage internalization rate varies depending on the phage type and the cell line. Notably, podovirus phage demonstrates the highest rate of internalization, while myovirus phage exhibits the lowest. Internalized phages maintain significant activity against intracellular bacteria. RNA sequencing revealed that phage-treated A549 cells display anti-inflammatory transcriptional signatures (immunobarcodes). Conversely, macrophages treated with siphovirus phage CK02 or podovirus phage CK21 demonstrate an anti-inflammatory profile, while those treated with myovirus phage CK12 maintain a pro-inflammatory response. Moreover, both phage-treated cells exhibit the downregulation of cellular reproduction and proliferation pathways, pointing to underexplored dimensions of phage-mammalian cell interactions. Altogether, our findings highlight the complexity of phage effects on mammalian cells.