title: Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a.
abstract: Several reports have indicated that natural killer (NK) cells are of particular importance in the innate response against herpesvirus infections. As a consequence, herpesviruses have developed diverse mechanisms for evading NK cells, although few such mechanisms have been identified for the largest herpesvirus subfamily, the alphaherpesviruses. The antiviral activity of NK cells is regulated by a complex array of interactions between activating/inhibitory receptors on the NK cell surface and the corresponding ligands on the surfaces of virus-infected cells. Here we report that the US3 protein kinase of the alphaherpesvirus pseudorabies virus (PRV) displays previously uncharacterized immune evasion properties: it triggers the binding of the inhibitory NK cell receptor CD300a to the surface of the infected cell, thereby providing increased CD300a-mediated protection of infected cells against NK cell-mediated lysis. US3-mediated CD300a binding was found to depend on aminophospholipid ligands of CD300a and on group I p21-activated kinases. These data identify a novel alphaherpesvirus strategy for evading NK cells and demonstrate, for the first time, a role for CD300a in regulating NK cell activity upon contact with virus-infected target cells.
  
  
  OBJECTIVE
  Herpesviruses have developed fascinating mechanisms to evade elimination by key elements of the host immune system, contributing to their ability to cause lifelong infections with recurrent reactivation events. Natural killer (NK) cells are central in the innate antiviral response. Here we report that the US3 protein kinase of the alphaherpesvirus pseudorabies virus displays a previously uncharacterized capacity for evasion of NK cells. Expression of US3 protects infected cells from NK cell-mediated lysis via increased binding of the inhibitory NK cell receptor CD300a. We show that this US3-mediated increase in CD300a binding depends on aminophospholipids and on cellular p21-activated kinases (PAKs). The identification of this novel NK cell evasion strategy may contribute to the design of improved herpesvirus vaccines and may also have significance for other PAK- and CD300a-modulating viruses and cancer cells.
authors.affiliation: Department of Virology, Parasitology, and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Grauwet
authors.affiliation: IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Vitale
authors.affiliation: Department of Virology, Parasitology, and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: De Pelsmaeker
authors.affiliation: Department of Virology, Parasitology, and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Jacob
authors.affiliation: Department of Virology, Parasitology, and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Laval
authors.affiliation: IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Moretta
authors.affiliation: Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Parodi
authors.affiliation: Dipartimento di Medicina Molecolare e Traslazionale, University of Brescia, Brescia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Parolini
authors.affiliation: Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy Istituto Giannina Gaslini, Genoa, Italy Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Cantoni
authors.affiliation: Department of Virology, Parasitology, and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium herman.favoreel@ugent.be.
authors.forename: H W
authors.initials: HW
authors.lastname: Favoreel
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002460:Cell Line; D011558:Herpesvirus 1, Suid / Q000276:immunology* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007694:Killer Cells, Natural / Q000276:immunology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C515070:CD300A protein, human; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D014764:Viral Proteins; D011494:Protein Kinases