The CXCL8/MAPK/hnRNP-K axis enables susceptibility to infection by EV-D68, rhinovirus, and influenza virus in vitro.

Summary

This mechanistic study shows that CXCL8 engagement of CXCR1/2 activates MAPK signaling, driving hnRNP‑K cytoplasmic translocation and enhanced recognition of viral RNA, thereby promoting EV‑D68 replication, with similar effects in influenza and rhinovirus. Genetic or pharmacologic disruption of CXCL8/CXCR1/2 reduces viral replication in vitro, positioning the axis as a potential pan‑respiratory antiviral target.

Key Findings

• Silencing CXCL8 or CXCR1/2 significantly reduced EV‑D68 replication in vitro.
• CXCL8 signaling activated MAPK and drove nuclear-to-cytoplasmic translocation of hnRNP‑K, enhancing viral RNA recognition and 5′UTR function.
• The CXCL8/MAPK/hnRNP‑K axis also facilitated replication of influenza virus and rhinovirus, indicating a conserved pro‑viral pathway.

Clinical Implications

CXCL8/CXCR1/2 or downstream MAPK/hnRNP‑K modulation could be explored as host-directed antivirals against diverse respiratory viruses. Caution is needed to balance anti-inflammatory effects with essential immune functions when targeting CXCL8 signaling.

Limitations

• In vitro cell-based experiments without in vivo validation
• Potential off-target or pleiotropic effects when modulating CXCL8/MAPK pathways not fully characterized

Future Directions

Evaluate CXCR1/2 or MAPK inhibitors for antiviral efficacy in vivo; investigate tissue-specific roles and safety of CXCL8-axis modulation; assess synergy with direct-acting antivirals.