title: Inflammatory monocytes and NK cells play a crucial role in DNAM-1-dependent control of cytomegalovirus infection.
abstract: The poliovirus receptor (PVR) is a ubiquitously expressed glycoprotein involved in cellular adhesion and immune response. It engages the activating receptor DNAX accessory molecule (DNAM)-1, the inhibitory receptor TIGIT, and the CD96 receptor with both activating and inhibitory functions. Human cytomegalovirus (HCMV) down-regulates PVR expression, but the significance of this viral function in vivo remains unknown. Here, we demonstrate that mouse CMV (MCMV) also down-regulates the surface PVR. The m20.1 protein of MCMV retains PVR in the endoplasmic reticulum and promotes its degradation. A MCMV mutant lacking the PVR inhibitor was attenuated in normal mice but not in mice lacking DNAM-1. This attenuation was partially reversed by NK cell depletion, whereas the simultaneous depletion of mononuclear phagocytes abolished the virus control. This effect was associated with the increased expression of DNAM-1, whereas TIGIT and CD96 were absent on these cells. An increased level of proinflammatory cytokines in sera of mice infected with the virus lacking the m20.1 and an increased production of iNOS by inflammatory monocytes was observed. Blocking of CCL2 or the inhibition of iNOS significantly increased titer of the virus lacking m20.1. In this study, we have demonstrated that inflammatory monocytes, together with NK cells, are essential in the early control of CMV through the DNAM-1-PVR pathway.
authors: Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia.
authors: Tihana
authors: 0000-0002-3299-1334
authors: T
authors: Lenac Rovis
authors: Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia.
authors: Paola
authors: 0000-0002-9178-9128
authors: P
authors: Kucan Brlic
authors: The Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem 91120, Israel.
authors: Noa
authors: N
authors: Kaynan
authors: Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia.
authors: Vanda
authors: 0000-0002-7182-8927
authors: V
authors: Juranic Lisnic
authors: Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia.
authors: Ilija
authors: 0000-0001-8839-7839
authors: I
authors: Brizic
authors: Max von Pettenkofer-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany.
authors: Stefan
authors: S
authors: Jordan
authors: Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia Department of Virology, Hannover Medical School, 30625 Hannover, Germany.
authors: Adriana
authors: 0000-0001-9885-3535
authors: A
authors: Tomic
authors: Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia.
authors: Daria
authors: 0000-0001-5280-827X
authors: D
authors: Kvestak
authors: Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia.
authors: Marina
authors: 0000-0003-0747-7074
authors: M
authors: Babic
authors: The Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem 91120, Israel.
authors: Pinchas
authors: 0000-0001-8251-9292
authors: P
authors: Tsukerman
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors: Marco
authors: 0000-0001-5222-4987
authors: M
authors: Colonna
authors: Max von Pettenkofer-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany.
authors: Ulrich
authors: 0000-0001-9446-900X
authors: U
authors: Koszinowski
authors: Department of Virology, Hannover Medical School, 30625 Hannover, Germany.
authors: Martin
authors: M
authors: Messerle
authors: The Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem 91120, Israel.
authors: Ofer
authors: O
authors: Mandelboim
authors: Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia.
authors: Astrid
authors: 0000-0001-5470-5370
authors: A
authors: Krmpotic
authors: Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia stipan.jonjic@medri.uniri.hr.
authors: Stipan
authors: 0000-0001-5003-3108
authors: S
authors: Jonjic
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000209:etiology* / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D011991:Receptors, Virus / Q000037:antagonists & inhibitors / Q000502:physiology; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D011991:Receptors, Virus; C066100:poliovirus receptor; D018664:Interleukin-12; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse