Manipulation of CXCR4 signaling by human cytomegalovirus (HCMV) interleukin-10

Abstract

Abstract Herpesviruses have developed numerous strategies for manipulating host immune responses to avoid clearance and establish lifelong latent infection. Human cytomegalovirus (HCMV) encodes cmvIL-10, an ortholog of human interleukin-10 that binds to the cellular IL-10 receptor (IL-10R) with high affinity to elicit potent immunosuppressive effects, including inhibition of inflammatory cytokine production. In direct contrast, we found that cmvIL-10 promotes heightened chemokine signaling. CXCR4 is an essential cellular chemokine receptor that guides cell movement toward its natural ligand, CXCL12. We found that monocytes and epithelial cells exhibited significantly increased calcium mobilization and migration to CXCL12 in the presence of cmvIL-10. Treatment with a Stat3 inhibitor or siRNA blocked these effects, indicating that Stat3 activation is required for potentiation of CXCR4 signaling activity by cmvIL-10. Using immunofluorescence microscopy, we found evidence of association between IL-10R and CXCR4 in cell membranes and observed that cmvIL-10 treatment led to dramatic changes in the cellular distribution of Stat3. Since intracellular calcium release is a rapid response, Stat3 is likely acting here via a non-canonical pathway, rather than in its classic role as a transcription factor. These findings demonstrate that cmvIL-10 triggers a complex series of events that augment the signaling activity of a cellular chemokine receptor. Given that monocytes are a primary reservoir of latent virus, manipulation of CXCR4 signaling may enable HCMV to modify cell trafficking patterns to promote virus dissemination.