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. 2014 Sep;88(18):10990-4.
doi: 10.1128/JVI.01259-14. Epub 2014 Jul 9.

Human cytomegalovirus upregulates expression of the lectin galectin 9 via induction of beta interferon

Brian P McSharry  1 , Simone K Forbes  2 , John Z Cao  2 , Selmir Avdic  1 , Emily A Machala  1 , David J Gottlieb  3 , Allison Abendroth  1 , Barry Slobedman  4
Affiliations

Human cytomegalovirus upregulates expression of the lectin galectin 9 via induction of beta interferon

Brian P McSharry et al. J Virol. 2014 Sep.

Abstract

Regulation of the lectin galectin 9 (Gal-9) was investigated for the first time during human cytomegalovirus (HCMV) infection. Gal-9 transcription was significantly upregulated in transplant recipients with reactivated HCMV in vivo. In vitro, Gal-9 was potently upregulated by HCMV independently of viral gene expression, with interferon beta (IFN-β) identified as the mediator of this effect. This study defines an immunoregulatory protein potently increased by HCMV infection and a novel mechanism to control Gal-9 through IFN-β induction.

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Figures

FIG 1
FIG 1
Modulation of Gal-9 by HCMV infection (A) Relative levels of Gal-9 transcripts were determined by qRT-PCR in PBMCs isolated from peripheral blood drawn from allogeneic HSCT recipients at two early times after transplant (Pre-reactivation) and two time points later, after reactivation (Post-reactivation), for each of five recipients with detectable HCMV reactivation (reactivation-positive patients) and seven patients without detectable HCMV reactivation (reactivation-negative patients). Error bars indicate the standard error of the means. Significant differences in Gal-9 transcript levels at pre- and postreactivation time points were determined using a two-tailed, paired Student's t test (**, P < 0.005). (B) HFs were infected with HCMV at a multiplicity of infection (MOI) of 3 before analysis of Gal-9 transcript levels by qRT-PCR at 6 and 24 h p.i. (C) HFs were infected with HCMV and UV-HCMV at an MOI of 3 before Gal-9 transcript levels were determined by qRT-PCR at 24 h p.i. (D) Representative example of five independent replicates of immunoblotting for Gal-9 (R&D Systems) and GAPDH (Santa Cruz Biotechnology) proteins in mock-, HCMV-, and UV-HCMV-infected HFs at 24 and 48 h p.i. (E and F) Media from mock-, HCMV-, and UV-HCMV-infected HFs was harvested at 24 h p.i. and filtered through a 0.1-μm-pore-size filter before being added to new HF monolayers. Analyses of Gal-9 transcript levels at 24 h posttreatment (E) and protein levels at 48 h posttreatment (F) are depicted. Error bars indicate the standard error of the means. Significant differences in the results of treatments with HCMV and UV-HCMV from the results for mock treatment were determined using a two-tailed, paired Student's t test (*, P < 0.05).
FIG 2
FIG 2
Regulation of galectin 9 expression by HCMV (A) Parental HF, V-HF, or nPro-HF were infected at an MOI of 3 with HCMV or UV-HCMV before cell lysates were harvested at 48 h p.i. and immunoblotted for Gal-9 (R&D Systems) and GAPDH (Santa Cruz Biotechnology). (B) Media from mock-, HCMV-, or UV-HCMV-infected parental HFs were harvested at 24 h p.i. and filtered through a 0.1-μm-pore-size filter before being added to fresh HF, V-HF, or nPro-HF monolayers and incubated for 48 h before cell lysates were immunoblotted for Gal-9 and GAPDH. Blots are representative of at least 3 independent biological replicates. (C) HFs were mock, HCMV, or UV-HCMV infected in the presence of an IFN-β-blocking Ab or an isotype control. Cell lysates were harvested at 48 h p.i. before immunoblotting for Gal-9 and GAPDH. (D) HFs were treated with media from mock-, HCMV-, or UV-HCMV-infected cultures (harvested at 24 h p.i. and filtered through a 0.1-μm-pore-size filter) in the presence of an IFN-β-blocking Ab or an isotype control. Cell lysates were generated at 48 h postinfection/treatment before immunoblotting for Gal-9 and GAPDH. (E) HFs were treated with recombinant IFN-β at the concentrations indicated before immunoblotting for Gal-9 and GAPDH at 48 h posttreatment. HFs were also mock and HCMV infected in parallel as indicated. Blots are representative of at least 3 independent biological replicates.
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