title: Complexity of Host Micro-RNA Response to Cytomegalovirus Reactivation After Organ Transplantation.
abstract: Human (Homo sapiens) micro-RNAs (hsa-miRNAs) regulate virus and host-gene translation, but the biological impact in patients with human cytomegalovirus (hCMV) infection is not well defined in a clinically relevant model. First, we compared hsa-miRNA expression profiles in peripheral blood mononuclear cells from 35 transplant recipients with and without CMV viremia by using a microarray chip covering 847 hsa-miRNAs. This approach demonstrated a set of 142 differentially expressed hsa-miRNAs. Next, we examined the effect of each of these miRNAs on viral growth by using human fibroblasts (human foreskin fibroblast-1) infected with the hCMV Towne strain, identifying a subset of proviral and antiviral hsa-miRNAs. miRNA-target prediction software indicated potential binding sites within the hCMV genome (e.g., hCMV-UL52 and -UL100 [UL = unique long]) and host-genes (e.g., interleukin-1 receptor, IRF1). Luciferase-expressing plasmid constructs and immunoblotting confirmed several predicted miRNA targets. Finally, we determined the expression of selected proviral and antiviral hsa-miRNAs in 242 transplant recipients with hCMV-viremia. We measured hsa-miRNAs before and after antiviral therapy and correlated hsa-miRNA expression levels to hCMV-replication dynamics. One of six antiviral hsa-miRNAs showed a significant increase during treatment, concurrent with viral decline. In contrast, six of eight proviral hsa-miRNAs showed a decrease during viral decline. Our results indicate that a complex and multitargeted hsa-miRNA response occurs during CMV replication in immunosuppressed patients. This study provides mechanistic insight and potential novel biomarkers for CMV replication.
authors.affiliation: Li KaShing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.|Applied Microbiology Research, Department Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Egli
authors.affiliation: Li KaShing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: L F
authors.initials: LF
authors.lastname: Lisboa
authors.affiliation: Li KaShing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: D
authors.initials: D
authors.lastname: O'Shea
authors.affiliation: Department of Transplant Medicine, Section of Nephrology, Oslo University Hospital-Rikshospitalet, and Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Asberg
authors.affiliation: Department of Nephrology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Mueller
authors.affiliation: Department of Microbial and Cellular Sciences, University of Surrey, London, UK.
authors.forename: V
authors.initials: V
authors.lastname: Emery
authors.affiliation: Li KaShing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.|Department of Medicine and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Li KaShing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.|Department of Medicine and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Humar
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D015331:Cohort Studies; D003587:Cytomegalovirus / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology*; D006085:Graft Survival; D054884:Host-Pathogen Interactions; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D016377:Organ Transplantation / Q000009:adverse effects*; D011183:Postoperative Complications; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D014766:Viremia / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; D035683:MicroRNAs; D012333:RNA, Messenger; D012367:RNA, Viral
keywords: cytomegalovirus; micro-RNA