title: Hcmv-miR-UL22A-5p: A Biomarker in Transplantation With Broad Impact on Host Gene Expression and Potential Immunological Implications.
abstract: Cytomegalovirus (CMV) encodes multiple microRNAs. While these have been partially characterized in vitro, their relevance to clinical CMV infection has not been evaluated. We analyzed samples from a cohort of solid organ transplant patients with CMV disease (n = 245) for viral microRNA expression. Several CMV microRNAs were readily detectable in patients with CMV disease in variable relative abundance. Expression level generally correlated with DNA viral load and the absence of viral microRNA was associated with faster viral clearance. Detection of hcmv-miR-UL22A-5p at baseline independently predicted the recurrence of CMV viremia upon discontinuation of antiviral therapy (OR 3.024, 95% CI: 1.35-6.8; p = 0.007). A combination of direct mRNA targeting by the microRNA and indirect modulation of gene expression involving isoforms of the transcriptional regulator C-MYC may be responsible for the broad effects seen in the association of gene transcripts with the RNA-induced silencing complex and in global protein expression upon hcmv-miR-UL22A-5p transfection. This novel study of in vivo viral microRNA expression profiles provides unique insight into the complexity of clinical CMV infection following transplantation. We provide evidence that viral microRNAs may have complex effects on gene expression and be associated with specific virologic and clinical outcomes, and thus could be further evaluated as biomarkers.
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: L F
authors.initials: LF
authors.lastname: Lisboa
authors.affiliation: Infection Biology Lab, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Egli
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: D
authors.initials: D
authors.lastname: O'Shea
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.|Department of Transplant Medicine, Section for Nephrology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Åsberg
authors.affiliation: Department of Transplant Medicine, Section for Nephrology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Department of Microbiology, Oslo University Hospital Rikshospitalet , Oslo, and Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Rollag
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: X L
authors.initials: XL
authors.lastname: Pang
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: D L
authors.initials: DL
authors.lastname: Tyrrell
authors.affiliation: Multi-organ Transplant Program, University Health Network, Toronto, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Multi-organ Transplant Program, University Health Network, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Humar
mesh_terms: D015415:Biomarkers; D015153:Blotting, Western; D015331:Cohort Studies; D019295:Computational Biology; D003587:Cytomegalovirus / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000097:blood / Q000235:genetics* / Q000821:virology; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015967:Gene Expression Regulation, Viral; D006084:Graft Rejection; D006085:Graft Survival; D054884:Host-Pathogen Interactions / Q000235:genetics* / Q000276:immunology; D006801:Humans; D047468:Immunoprecipitation; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D016377:Organ Transplantation; D011379:Prognosis; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012008:Recurrence; D012307:Risk Factors; D014779:Virus Replication
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D012367:RNA, Viral
keywords: infection and infectious agents; infectious disease; molecular biology: micro RNA; molecular biology: transcription factor; translational research / science; viral: Cytomegalovirus (CMV)