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Immunomodulatory Function of Interleukin 28B During Primary Infection With Cytomegalovirus

Egli, Adrian ; Levin, Aviad ; Santer, Deanna M. ; Joyce, Michael ; O'Shea, Daire ; Thomas, Brad S. ; Lisboa, Luiz F. ; Barakat, Khaled ; Bhat, Rakesh ; Fischer, Karl P. ; Houghton, Michael ; Tyrrell, D. Lorne ; Kumar, Deepali ; Humar, Atul

In: The Journal of Infectious Diseases

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    Titre
    • Immunomodulatory Function of Interleukin 28B During Primary Infection With Cytomegalovirus
    Auteur
    • Egli, Adrian. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
    • Levin, Aviad. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
    • Santer, Deanna M.. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
    • Joyce, Michael. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
    • O'Shea, Daire. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
    • Thomas, Brad S.. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
    • Lisboa, Luiz F.. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
    • Barakat, Khaled. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
    • Bhat, Rakesh. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
    • Fischer, Karl P.. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
    • Houghton, Michael. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
    • Tyrrell, D. Lorne. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
    • Kumar, Deepali. Department of Medicine and Multi-organ Transplant Program, University Health Network, Toronto, Ontario, Canada
    • Humar, Atul. Department of Medicine and Multi-organ Transplant Program, University Health Network, Toronto, Ontario, Canada
    Type de document
    • Postprint
    Identifiant OAI-PMH
    • oai:doc.rero.ch:303566
    Summary
    Background. Feedback mechanisms between interferons α and λ (IFNs) may be affected by single nucleotide polymorphisms (SNP) in interleukin 28B (IL-28B; IFN-λ3) promoter region and may influence cytomegalovirus (CMV) replication. Methods. We associated IL-28B SNPs with the risk of CMV replication after transplantation. Next, we examined the effect of IL-28B genotypes on IL-28B, and IFN-stimulated gene (ISG) expression, and CMV replication in human foreskin fibroblast (HFF) and peripheral blood mononuclear cells (PBMCs). Results. Transplant recipients with an IL-28B SNP (rs8099917) had significantly less CMV replication (P = .036). Both HFF-cells and PBMCs with a SNP showed lower IL-28B expression during infection with CMV, but higher "antiviral” ISG expression (eg, OAS1). Fibroblasts with a SNP had a 3-log reduction of CMV replication at day 4 (P = .004). IL-28B pretreatment induced ISG expression in noninfected fibroblasts, but a relative decrease of ISG expression could be observed in CMV-infected fibroblasts. The inhibitory effects of IL-28B could be abolished by siRNA or antagonistic peptides against the IL-28 receptor. In fibroblasts, inhibition of IL-28 signaling resulted in an increase of ISG expression and 3-log reduction of CMV-replication (P = .01). Conclusions. We postulate that IL-28B may act as a key regulator of ISG expression during primary CMV infection. IL-28B SNPs may be associated with higher antiviral ISG expression, which results in better replication control