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Function Selectivity for Neutrophil Signaling and Chemokines, Vcxcl Novel Human Cytomegalovirus Viral Chemokines, vCXCL-1s, Display Functional Selectivity for Neutrophil Signaling and Function This information is current as of October 2, 2021. Jinho Heo, Pranay Dogra, Tom J. Masi, Elisabeth A. Pitt, Petra de Kruijf, Martine J. Smit and Tim E. Sparer J Immunol 2015; 195:227-236; Prepublished online 18 May 2015; doi: 10.4049/jimmunol.1400291 Downloaded from http://www.jimmunol.org/content/195/1/227 References This article cites 70 articles, 34 of which you can access for free at: http://www.jimmunol.org/content/195/1/227.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 2, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Novel Human Cytomegalovirus Viral Chemokines, vCXCL-1s, Display Functional Selectivity for Neutrophil Signaling and Function Jinho Heo,*,1 Pranay Dogra,* Tom J. Masi,* Elisabeth A. Pitt,* Petra de Kruijf,† Martine J. Smit,† and Tim E. Sparer* 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, Downloaded from 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 (b-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. The Journal of Immu- http://www.jimmunol.org/ nology, 2015, 195: 227–236. uman CMVs (HCMVs) are ubiquitous pathogens that are ceptor recognition and activation (15, 16). We hypothesized that well adapted to modulate host immune responses (1, 2). hypervariable vCXCL-1s produced from HCMV-infected endothe- H HCMV contains genes for immune evasion that function lial cells recruit neutrophils with alterations in binding, activation, to increase viral survival and dissemination and that may con- and neutrophil functions that contribute to viral dissemination and tribute to pathogenesis (3). There are a large number of open possibly its pathogenesis. ∼ reading frames (ORFs; 82) in HCMV that are nonessential for Eleven distinct vCXCL-1 clades were previously found in by guest on October 2, 2021 virus replication in vitro, but may have a role in immune evasion clinical isolates from congenitally infected infants (17). In these in vivo (4, 5). In one of these regions, the UL/b’ region, the ORFs groups the N-loop region was highly variable. In addition one UL146 and UL147 have limited homology to host CXC chemo- isolate, vCXCL-1TX15, encoded a non-ELR CXC chemokine. kines (5). Yet, the UL146 protein from the Toledo strain of HCMV, Although the genetic variability of vCXCL-1 does not correlate vCXCL-1Toledo, acts as a functional CXC chemokine (6) that binds definitively with congenital outcomes, the hypervariability within to CXCR1 and CXCR2 and induces neutrophil chemotaxis and the N-loop region suggests that the vCXCL-1s may have different calcium mobilization (7). This gene is one of the most variable in interactions with the chemokine receptors CXCR1 and CXCR2. the entire HCMV genome (8–12). This variability is localized To address functional variability of the vCXCL-1s, recombinant throughout the entire chemokine, including the N terminus and vCXCL-1s from each clade were generated. Competition binding, N-loop region, which are important for chemokine receptor signaling, and neutrophil activation assays were used to assess the binding and activation (13, 14). Some strains even alter the Glu- effect of vCXCL1 variability on chemokine function. Leu-Arg (ELR) prior to the CXC motif, which is critical for re- Materials and Methods Materials *Department of Microbiology, The University of Tennessee, Knoxville, TN 37996; † and Division of Medicinal Chemistry, VU University Amsterdam, 1081 HV Amster- DMEM, penicillin, and streptomycin were obtained from Hyclone Labora- dam, the Netherlands tories (Logan, UT). FBS was purchased from Mediatech (Manassas, VA). 1 Current address: Department of Radiation Oncology, University of Virginia, DMEM containing 25 mM HEPES and L-glutamine, OPTI-MEM, Charlottesville, VA. Hygromycin B, and Geneticin were obtained from Invitrogen (Paisley, Received for publication February 5, 2014. Accepted for publication April 27, 2015. U.K.). BSA Fraction V (BSA) was purchased from Roche (Mannheim, Germany). Polyethylenimine was obtained from Polysciences (Warrington, PA). This work was supported by National Institutes of Health–National Institute of Al- 125 35 lergy and Infectious Diseases Grant 1RO1A1071042-01A2 and American Heart As- I-CXCL8 and S-GTPgS was obtained from PerkinElmer Life Sciences sociation Grant 043518N (to J.H., T.J.M., P.D., and T.E.S.) and by the Netherlands (Boston, MA). Organisation for Scientific Research (M.J.S.). Clinical isolates used for cloning of the vCXCL-1 ORFs were provided by Dr. James Bale (University of Utah School of Medicine), Dr. Sunwen Address correspondence and reprint requests to Dr. Tim E. Sparer, University of Tennessee, 1414 Cumberland Avenue, Knoxville, TN 37996. E-mail: tsparer@ Chou, (Oregon Health and Science University), and Dr. Gail J. Demmler utk.edu (Texas Children’s Hospital) as described previously (17). Abbreviations used in this article: ELR, Glu-Leu-Arg; HCMV, human CMV; ORF, Cell culture and CXCR2 transfection open reading frame; PBN, peripheral blood neutrophil. Insect cells (serum-free adapted SF9 cells; Invitrogen, Carlsbad, CA) were Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 grown at 28˚C in serum-free Sf-900 II SFM medium (Invitrogen). Hi5 cells www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400291 228 NOVEL CMV CHEMOKINES DIFFERENTIALLY ACTIVATE NEUTROPHILS (Invitrogen) were grown in suspension at 28˚C in serum-free Insect- of the modified Boyden chamber (Neuroprobe, Gaithersburg, MD) and XPRESS medium (Lonza, Basel, Switzerland). Both cells were grown in fitted with a 5-mm filter. PBNs were labeled with 1:1000 CalceinAM a nonhumidified, ambient air–regulated incubator. (Invitrogen) for 1 h on a rotating wheel at 37˚C. Cells were washed with PathHunter HEK293-CXCR2 cells (DiscoveRx, Fremont, CA), were PBS and resuspended to 5 3 106 cells/ml; 20 ml of cells was added to the grown at 5% CO2 and 37˚C in DMEM with 25 mM HEPES and L-glu- upper well. The PBNs were allowed to migrate for 2–3 h at 37˚C. The tamine supplemented with 10% (v/v) heat-inactivated FBS, 50 IU/ml number of PBNs that migrated to the chemokines was measured on a fluo- penicillin, 50 mg/ml streptomycin, 800 mg/ml Geneticin, and 200 mg/ml rescent plate reader (Synergy 2; Biotek) minus the fluorescence from the Hygromycin B. buffer-only control wells. HL-60 T2 cell transfectants overexpressing CXCR2 (a gift from Dr. Ann Receptor binding analysis Richmond, Vanderbilt University) were grown at 5% CO2 and 37˚C in RPMI 1640 (Hyclone Laboratories) supplemented with 10% (v/v) FBS, 50 IU/ml The ability of vCXCL-1s to compete for binding to either CXCR1 or penicillin, 50 mg/ml streptomycin, and 400 mg/ml G418 (Mediatech). 5 35 CXCR2 was evaluated as described previously (6). Briefly, 1 3 10 to 3 3 g 5 For S-GTP S experiments, HEK293T cells were grown at 5% CO2 10 HEK293 cells stably overexpressing CXCR1 or CXCR2 were incu- and 37˚C in DMEM supplemented with 10% (v/v) FBS, 50 IU/ml peni- bated with 100 pM 125I-labeled CXCL8 (MP Biomedical) and increasing m cillin, and 50 g/ml streptomycin. HEK293T cells were transiently concentrations of unlabeled chemokines for 1 h at room temperature. Cells m transfected with 2.5 g cDNA encoding human CXCR2 supplemented were collected on glass filters and washed twice, and bound radioactivity with 2.5 mg pcDEF3 by using linear polyethylenimine with an m.w. of 25 was measured with liquid scintillation counting. The graph was plotted, kDa as described previously (18). and competition constants (IC50) were analyzed using GraphPad Prism 5 Neutrophil isolation for Windows. 35 Peripheral blood neutrophils (PBNs) were isolated from EDTA-treated S-GTPgS binding assay blood from healthy human volunteers using dextran sedimentation and Two days after transfection with CXCR2 expression constructs, HEK293T density gradient centrifugation as previously described (19).
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