title: Modulation of Clr Ligand Expression and NKR-P1 Receptor Function during Murine Cytomegalovirus Infection.
abstract: Viruses are known to induce pathological cellular states that render infected cells susceptible or resistant to immune recognition. Here, we characterize an MHC-I-independent natural killer (NK) cell recognition mechanism that involves modulation of inhibitory NKR-P1B:Clr-b receptor-ligand interactions in response to mouse cytomegalovirus (MCMV) infection. We demonstrate that mouse Clr-b expression on healthy cells is rapidly lost at the cell surface and transcript levels in a time- and dose-dependent manner upon MCMV infection. In addition, cross-species infections using rat cytomegalovirus (RCMV) infection of mouse fibroblasts and MCMV infection of rat fibroblasts suggest that this response is conserved during host-pathogen interactions. Active viral infection appears to be necessary for Clr-b loss, as cellular stimulation using UV-inactivated whole virus or agonists of many innate pattern recognition receptors failed to elicit efficient Clr-b downregulation. Notably, Clr-b loss could be partially blocked by titrated cycloheximide treatment, suggesting that early viral or nascent host proteins are required for Clr-b downregulation. Interestingly, reporter cell assays suggest that MCMV may encode a novel Clr-b-independent immunoevasin that functionally engages the NKR-P1B receptor. Together, these data suggest that Clr-b modulation is a conserved innate host cell response to virus infection that is subverted by multiple CMV immune evasion strategies.
authors.affiliation: Department of Immunology, University of Toronto, and Sunnybrook Research Institute, Toronto, Ont., Canada.
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Aguilar
authors.forename: Aruz
authors.initials: A
authors.lastname: Mesci
authors.forename: Jaehun
authors.initials: J
authors.lastname: Ma
authors.forename: Peter
authors.initials: P
authors.lastname: Chen
authors.forename: Christina L
authors.initials: CL
authors.lastname: Kirkham
authors.forename: Joachim
authors.initials: J
authors.lastname: Hundrieser
authors.forename: Sebastian
authors.initials: S
authors.lastname: Voigt
authors.forename: David S J
authors.initials: DS
authors.lastname: Allan
authors.forename: James R
authors.initials: JR
authors.lastname: Carlyle
mesh_terms: D000818:Animals; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D057131:Immune Evasion; D051379:Mice; D018146:Muromegalovirus / Q000276:immunology*; D041681:NIH 3T3 Cells; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000235:genetics / Q000276:immunology*; D051381:Rats
chemical_list: D058286:Calcitonin Receptor-Like Protein; D055651:NK Cell Lectin-Like Receptor Subfamily B