Can increasing particular host proteins help the H9N2 bird flu virus replicate in human cells?

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Avian influenza viruses circulate naturally among migratory wild birds but occasionally infect other species, including poultry, a broad range of mammals, and humans. Highly pathogenic avian influenza viruses (AIVs) are known to infect humans, but low-pathogenic AIVs—particularly the H7N9 and H9N2 subtypes—have also caused human infections and remain a zoonotic risk.

In this laboratory cell-line study, researchers used single-cell transcriptomics to examine responses in human A549 cells and chicken DF-1 cells 24 h after infection with the zoonotic H9N2 virus. The two cell lines showed distinct transcriptional responses.

The genes for dipeptidyl peptidase-4 (DPP4) and carboxypeptidase Q (CPQ) were expressed at significantly higher levels in infected DF-1 cells than in A549 cells, suggesting a potential role in viral replication. In gene-overexpression experiments, overexpression of CPQ and DPP4 in A549 cells resulted in significantly greater H9N2 viral replication than in H9N2-infected, mock-transfected wild-type cells.

Gene Set Enrichment Analysis of differentially expressed genes also revealed downregulation of lipid metabolism pathways in cell clusters with high expression of H9N2 viral genes in both A549 and DF-1 cells. This suggests a potential link between host lipid metabolism and H9N2 replication.

The results provide insights into the transcriptional responses of A549 and DF-1 cells to H9N2 infection and identify candidate host factors and pathways associated with viral replication. They provide a foundation for future studies using physiologically relevant models to investigate the cellular determinants of H9N2 infection.