Viral hijacking: how cmvIL-10 supercharges CXCR4 signaling 2755

Abstract Description Cytokines and chemokines orchestrate immune responses to recognize and eliminate pathogens, but pathogens, like human cytomegalovirus (HCMV), exploit these pathways. HCMV, a herpesvirus that establishes lifelong latent infection, encodes cmvIL-10, an ortholog of human interleukin-10 that binds the cellular IL-10 receptor (cIL-10R), exerting immunosuppressive effects such as reduced inflammatory cytokine production and impaired dendritic cell activation. Notably, cmvIL-10 also enhances host CXCR4 signaling. CXCR4, a key chemokine receptor, mediates cell migration toward its primary ligand, CXCL12 (SDF-1). In monocytes and epithelial cells co-expressing cIL-10R and CXCR4, cmvIL-10 significantly increased calcium mobilization and migration to CXCL12. We further evaluated whether cmvIL-10 could amplify responses to other CXCR4 ligands, including macrophage migration inhibitory factor (MIF), trefoil factor family 2 (TFF2), and extracellular ubiquitin (UB). UB, MIF and TFF2 signaling triggered significant cell proliferation, and these responses were much greater in the presence of cmvIL-10. MIF and TFF2 also stimulated migration that was enhanced by cmvIL-10. These findings highlight the complex crosstalk between cytokine and chemokine signaling, underscoring HCMV’s ability to manipulate host immunity. A deeper understanding of these mechanisms is essential for developing effective vaccines and therapeutics. Funding Sources This project was funded by Biology Faculty Development Funds and the Research Enhancement Program at TWU (JVS). We also thank the Jane Nelson Institute for Women’s Leadership for support for KHS. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)