Cytomegalovirus CC chemokine promotes immune cell migration.

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  • Additional Information
    • Source:
      Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE
    • Publication Information:
      Publication: Washington Dc : American Society For Microbiology
      Original Publication: Baltimore, American Society for Microbiology.
    • Subject Terms:
      Cell Movement*; CD4-Positive T-Lymphocytes/*immunology ; Chemokines, CC/*immunology ; Muromegalovirus/*immunology ; Muromegalovirus/*pathogenicity ; Virulence Factors/*immunology ; Virulence Factors/*metabolism; Animals ; Chemokines, CC/genetics ; Chemokines, CC/metabolism ; DNA Mutational Analysis ; Disease Models, Animal ; Heart Transplantation/adverse effects ; Herpesviridae Infections/complications ; Herpesviridae Infections/pathology ; Herpesviridae Infections/virology ; Male ; Muromegalovirus/genetics ; Mutant Proteins/genetics ; Mutant Proteins/immunology ; Mutant Proteins/metabolism ; Protein Binding ; Rats ; Receptors, CCR/metabolism ; Sclerosis/immunology ; Sclerosis/pathology ; Sclerosis/virology ; Vascular Diseases/immunology ; Vascular Diseases/pathology ; Vascular Diseases/virology ; Viral Proteins/genetics ; Viral Proteins/immunology ; Viral Proteins/metabolism ; Virulence Factors/genetics
    • Abstract:
      Cytomegaloviruses manipulate the host chemokine/receptor axis by altering cellular chemokine expression and by encoding multiple chemokines and chemokine receptors. Similar to human cytomegalovirus (HCMV), rat cytomegalovirus (RCMV) encodes multiple CC chemokine-analogous proteins, including r129 (HCMV UL128 homologue) and r131 (HCMV UL130 and MCMV m129/130 homologues). Although these proteins play a role in CMV entry, their function as chemotactic cytokines remains unknown. In the current study, we examined the role of the RCMV chemokine r129 in promoting cellular migration and in accelerating transplant vascular sclerosis (TVS) in our rat heart transplant model. We determined that r129 protein is released into culture supernatants of infected cells and is expressed with late viral gene kinetics during RCMV infection and highly expressed in heart and salivary glands during in vivo rat infections. Using the recombinant r129 protein, we demonstrated that r129 induces migration of lymphocytes isolated from rat peripheral blood, spleen, and bone marrow and from a rat macrophage cell line. Using antibody-mediated cell sorting of rat splenocytes, we demonstrated that r129 induces migration of naïve/central memory CD4(+) T cells. Through ligand-binding assays, we determined that r129 binds rat CC chemokine receptors CCR3, CCR4, CCR5, and CCR7. In addition, mutational analyses identified functional domains of r129 resulting in recombinant proteins that fail to induce migration (r129-ΔNT and -C31A) or alter the chemotactic ability of the chemokine (r129-F43A). Two of the mutant proteins (r129-C31A and -ΔNT) also act as dominant negatives by inhibiting migration induced by wild-type r129. Furthermore, infection of rat heart transplant recipients with RCMV containing the r129-ΔNT mutation prevented CMV-induced acceleration of TVS. Together our findings indicate that RCMV r129 is highly chemotactic, which has important implications during RCMV infection and reactivation and acceleration of TVS.
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    • Grant Information:
      R01 HL085451 United States HL NHLBI NIH HHS; R01 HL083194 United States HL NHLBI NIH HHS; R01 HL088603 United States HL NHLBI NIH HHS; HL 088603 United States HL NHLBI NIH HHS; R01 HL066238 United States HL NHLBI NIH HHS; HL 66238-01 United States HL NHLBI NIH HHS; HL 083194 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (Chemokines, CC)
      0 (Mutant Proteins)
      0 (Receptors, CCR)
      0 (Viral Proteins)
      0 (Virulence Factors)
    • Publication Date:
      Date Created: 20120824 Date Completed: 20130107 Latest Revision: 20211021
    • Publication Date:
      20221213
    • Accession Number:
      PMC3486311
    • Accession Number:
      10.1128/JVI.00452-12
    • Accession Number:
      22915808