Hypoxia-inducible factor-1α exacerbates immune injury induced by influenza A virus and Streptococcus pneumoniae coinfection.

BACKGROUND

Influenza A virus (IAV) and Streptococcus pneumoniae (S. pneumoniae) coinfection during influenza pandemics is a significant contributor to mortality, mainly due to uncontrolled pathogen replication and an exaggerated immune response that often culminates in a cytokine storm. Hypoxia-inducible factor-1α (HIF-1α), a key regulator of cellular responses to hypoxia, has been implicated in various inflammatory processes; however, its role in pneumonia induced by IAV and S. pneumoniae coinfection remains unclear.

RESULTS

In this study, we established a model of IAV-S. pneumoniae coinfection and interfered with HIF-1α expression. The coinfection markedly increased both the expression and nuclear translocation of HIF-1α, which was accompanied by upregulated secretion of proinflammatory cytokines and exacerbated lung inflammation. Treatment with 2-ME2, a HIF-1α signaling inhibitor, attenuated the inflammatory responses in coinfection mice. Conversely, treatment with DMOG, a HIF-1α activator, exacerbated inflammation. Furthermore, we predicted downstream target genes of HIF-1α associated with infection and inflammatory responses, and validated the downregulation of a hub gene, Toll-like receptor 2 (TLR2), during IAV-S. pneumoniae coinfection.

CONCLUSION

Overall, this study demonstrates that upregulation of HIF-1α is strongly associated with severe inflammatory responses in IAV-S. pneumoniae coinfection, highlighting its potential as a therapeutic target for mitigating inflammation-related pathology in coinfected hosts. CLINICAL TRIAL NUMBER: Not applicable.