A CXCL8 Signaling Axis Enables Susceptibility to Infection by Human Respiratory Viruses

Respiratory viruses pose an ongoing threat to human health, with excessive cytokine secretion playing a critical role in severe illness and mortality. However, the complex relationship between cytokine secretion and viral infection remains poorly understood. Here, we have unraveled the role of cxcl8 as an early response gene to respiratory EV-D68 infection. The upregulation of CXCL8 by viral infection is found to be crucial for EV-D68 replication. Importantly, silencing CXCL8 or its receptors, CXCR1/2, significantly impedes EV-D68 replication. Upon recognition of CXCL8 by CXCR1/2, the MAPK pathway is activated, facilitating the translocation of the essential host cofactor hnRNP K from the nucleus to the cytoplasm. This translocation enhances the recognition of viral RNA by hnRNP K in the cytoplasm, promoting the functionality of the 5’UTR region in the viral genome. Interestingly, the VP4 structural protein of EV-D68 contains a mimic motif of human immunoreceptor tyrosine-based activation motif (ITAM) that interacts with syk and triggers the PI3K/AKT signaling pathway, resulting in elevated CXCL8 gene expression for viral replication. Moreover, our investigations reveal the conservation and significance of the CXCL8 signaling pathway across various prominent human respiratory viruses, including SARS-CoV-2, influenza, and rhinovirus. In summary, our findings unveil a paradigmatic mechanism through which respiratory viruses exploit cytokine-mediated intercellular communication to transmit signals that optimize viral replication. This deepens our understanding of the shared evolutionary strategies employed by respiratory viruses and opens up new avenues for the development of broad-spectrum antiviral drugs targeting respiratory pathogens.