title: Novel Human Cytomegalovirus Viral Chemokines, vCXCL-1s, Display Functional Selectivity for Neutrophil Signaling and Function.
abstract: Human CMV (HCMV) uses members of the hematopoietic system including neutrophils for dissemination throughout the body. HCMV encodes a viral chemokine, vCXCL-1, that is postulated to attract neutrophils for dissemination within the host. The gene encoding vCXCL-1, UL146, is one of the most variable genes in the HCMV genome. Why HCMV has evolved this hypervariability and how this affects the virus' dissemination and pathogenesis is unknown. Because the vCXCL-1 hypervariability maps to important binding and activation domains, we hypothesized that vCXCL-1s differentially activate neutrophils, which could contribute to HCMV dissemination, pathogenesis, or both. To test whether these viral chemokines affect neutrophil function, we generated vCXCL-1 proteins from 11 different clades from clinical isolates from infants infected congenitally with HCMV. All vCXCL-1s were able to induce calcium flux at a concentration of 100 nM and integrin expression on human peripheral blood neutrophils, despite differences in affinity for the CXCR1 and CXCR2 receptors. In fact, their affinity for CXCR1 or CXCR2 did not correlate directly with chemotaxis, G protein-dependent and independent (β-arrestin-2) activation, or secondary chemokine (CCL22) expression. Our data suggest that vCXCL-1 polymorphisms affect the binding affinity, receptor usage, and differential peripheral blood neutrophil activation that could contribute to HCMV dissemination and pathogenesis.
authors.affiliation: Department of Microbiology, The University of Tennessee, Knoxville, TN 37996; and.
authors.forename: Jinho
authors.initials: J
authors.lastname: Heo
authors.affiliation: Department of Microbiology, The University of Tennessee, Knoxville, TN 37996; and.
authors.forename: Pranay
authors.initials: P
authors.lastname: Dogra
authors.affiliation: Department of Microbiology, The University of Tennessee, Knoxville, TN 37996; and.
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Masi
authors.affiliation: Department of Microbiology, The University of Tennessee, Knoxville, TN 37996; and.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Pitt
authors.affiliation: Division of Medicinal Chemistry, VU University Amsterdam, 1081 HV Amsterdam, the Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: de Kruijf
authors.affiliation: Division of Medicinal Chemistry, VU University Amsterdam, 1081 HV Amsterdam, the Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
authors.affiliation: Department of Microbiology, The University of Tennessee, Knoxville, TN 37996; and tsparer@utk.edu.
authors.forename: Tim E
authors.initials: TE
authors.lastname: Sparer
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D054422:Chemokine CCL22 / Q000235:genetics / Q000276:immunology; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology*; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005786:Gene Expression Regulation; D014644:Genetic Variation; D057809:HEK293 Cells; D018922:HL-60 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D007223:Infant; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology / Q000821:virology; D061251:Primary Cell Culture; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000276:immunology*; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D061987:Sf9 Cells; D015398:Signal Transduction; D018411:Spodoptera; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D019390:Arrestins; C515482:CCL22 protein, human; D054422:Chemokine CCL22; D019743:Chemokines, CXC; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D011994:Recombinant Proteins; D014764:Viral Proteins; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C121017:viral chemokine CXC-1, Cytomegalovirus; D002118:Calcium