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Am J Transplant. 2016 Feb;16(2):650-60. doi: 10.1111/ajt.13464. Epub 2015 Oct 13.

Complexity of Host Micro-RNA Response to Cytomegalovirus Reactivation After Organ Transplantation.

Author information

1
Li KaShing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
2
Applied Microbiology Research, Department Biomedicine, University of Basel, Basel, Switzerland.
3
Department of Transplant Medicine, Section of Nephrology, Oslo University Hospital-Rikshospitalet, and Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
4
Department of Nephrology, University Hospital of Zurich, Zurich, Switzerland.
5
Department of Microbial and Cellular Sciences, University of Surrey, London, UK.
6
Department of Medicine and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.

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.

KEYWORDS:

cytomegalovirus; micro-RNA

PMID:
26460801
DOI:
10.1111/ajt.13464
[Indexed for MEDLINE]
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