Human Cytomegalovirus Upregulates Expression of the Lectin Galectin 9 via Induction of Beta Interferon

McSharry, Brian P.; Forbes, Simone K.; Cao, John Z.; Avdic, Selmir; Machala, Emily A.; Gottlieb, David; Abendroth, Allison; Slobedman, Barry

doi:10.1128/jvi.01259-14

Cited by 20 publications

(23 citation statements)

References 28 publications

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“…Although Galectin‐9 appears to be constitutively expressed in several organs including the spleen, it is possible that the levels of Galectin‐9 expressed in naive mice are not sufficient to induce apoptosis through Tim‐3. Studies by others have shown that Galectin‐9 expression is up‐regulated by inflammatory cytokines or viral infections . Therefore, we also tested whether Tim‐3 + Th1 cells were prone toward apoptosis in the context of acute LCMV infection, which induces a robust inflammatory response.…”

Section: Discussionmentioning

confidence: 98%

“…Studies by others have shown that Galectin-9 expression is up-regulated by inflammatory cytokines or viral infections. [66][67][68][69][70][71][72][73][74] Therefore, we also tested whether Tim-3 + Th1 cells were prone toward apoptosis in the context of acute LCMV infection, which induces a robust inflammatory response. Again, we found no evidence for Tim-3 + Th1 cells being more sensitive to apoptosis compared with Tim-3 À cells.…”

Section: Discussionmentioning

confidence: 99%

“…For intracellular staining of T-bet, cells were cultured and processed as described above except cells were fixed and permeabilized using the Foxp3/Transcription Factor Staining Buffer Set (eBioscience). For CD107a staining, anti-CD107a was added to cells along with LCMV GP [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] peptide and GolgiStop when cultures were initiated, and then cells were incubated for 5 hr at 37°in a 5% CO 2 incubator. Cells were then harvested, washed and stained for cell surface markers.…”

Section: Ex Vivo Stimulation and Functional Analysis Of Smarta Cellsmentioning

confidence: 99%

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Acute stimulation generates Tim‐3‐expressing T helper type 1 CD4 T cells that persist in vivo and show enhanced effector function

Gorman

Colgan

2018

Immunology

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T-cell immunoglobulin and mucin domain 3 (Tim-3) is a surface receptor expressed by T helper type 1 (Th1) effector CD4 T cells, which are critical for defence against intracellular pathogens and have been implicated in autoimmune disease. Previous studies showed that Tim-3 expression makes Th1 cells more susceptible to apoptosis and also marks functionally impaired T cells that arise due to chronic stimulation. However, other studies suggested that Tim-3-expressing Th1 cells do not always have these properties. To further define the relationship between Tim-3 and Th1 cell function, we analysed the characteristics of Th1 cells that expressed Tim-3 in response to brief stimulation in vitro or an acute viral infection in vivo. As expected, cultured CD4 T cells began expressing Tim-3 during Th1 differentiation and secondary stimulation generated Tim-3 and Tim-3 fractions that were separated and further analysed. When injected into naive mice, Tim-3 cells down-regulated Tim-3 and survived equally well compared with Tim-3 cells. Further, Tim-3 and Tim-3 Th1 cells had similar functional responses when transferred into naive mice that were subsequently infected with lymphocytic choriomeningitis virus (LCMV). Cultured Th1 cells that expressed Tim-3 following T-cell receptor stimulation had a greater capacity to express signature Th1 cytokines than their Tim-3 counterparts and showed differential expression of genes that regulate CD4 T-cell function. Consistent with these findings, Tim-3 Th1 cells generated in response to LCMV infection displayed augmented effector function relative to Tim-3 cells. These results suggest that Tim-3 expression by Th1 cells responding to acute stimulation can mark cells that are functionally competent and have an augmented ability to produce cytokines.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Ex Vivo Stimulation and Functional Analysis Of Smarta Cellsmentioning

confidence: 99%

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Acute stimulation generates Tim‐3‐expressing T helper type 1 CD4 T cells that persist in vivo and show enhanced effector function

Gorman

Colgan

2018

Immunology

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“…To interrogate the IFN-independent, IRF3-dependent response to HCMV HFs have been engineered (92,93) to lack either IRF3 through expression of the nPro protein of bovine viral diarrhea virus (BVDV) (nPro/HFs) which binds and degrades IRF3 (94) or STAT1, by expression of the parainfluenza virus type 5 (PIV-5) V protein (V/HFs) which targets STAT1 for proteasomal degradation (95). These nPro/HFs and V/HFs were recently utilized, alongside IRF3 KO CRISPR/Cas9 HFs, to demonstrate that expression of viperin, ISG15, IFIT1, IFIT2, IFIT3, Mx1, and Mx2 mRNA during infection with HCMV can be induced in an IRF3-dependent, STAT1-independent manner (96).…”

Section: Figure 1 | Induction and Subversion Of The Innate Ifn Responmentioning

confidence: 99%

Interferon-Independent Innate Responses to Cytomegalovirus

et al. 2019

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The critical role of interferons (IFNs) in mediating the innate immune response to cytomegalovirus (CMV) infection is well established. However, in recent years the functional importance of the IFN-independent antiviral response has become clearer. IFN-independent, IFN regulatory factor 3 (IRF3)-dependent interferon-stimulated gene (ISG) regulation in the context of CMV infection was first documented 20 years ago. Since then several IFN-independent, IRF3-dependent ISGs have been characterized and found to be among the most influential in the innate response to CMV. These include virus inhibitory protein, endoplasmic reticulum-associated IFN-inducible (viperin), ISG15, members of the interferon inducible protein with tetratricopeptide repeats (IFIT) family, interferon-inducible transmembrane (IFITM) proteins and myxovirus resistance proteins A and B (MxA, MxB). IRF3-independent, IFN-independent activation of canonically IFN-dependent signaling pathways has also been documented, such as IFN-independent biphasic activation of signal transducer and activator of transcription 1 (STAT1) during infection of monocytes, differential roles of mitochondrial and peroxisomal mitochondrial antiviral-signaling protein (MAVS), and the ability of human CMV (HCMV) immediate early protein 1 (IE1) protein to reroute IL-6 signaling and activation of STAT1 and its associated ISGs. This review examines the role of identified IFN-independent ISGs in the antiviral response to CMV and describes pathways of IFN-independent innate immune response induction by CMV.

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“…In addition, V/HF did not respond to IFNs even when stimulated with 1,000 pg/ml of IFN-␤ as determined by monitoring the relative mRNA levels of the ISGs protein kinase R (PKR) and ISG15 by quantitative reverse transcription-PCR (qRT-PCR) ( Fig. 1B and C) using a published protocol (32). The sequences of the primers used are indicated: GAPDH-F, 5=-TGTTCGTCATGGGT GTGAAC-3=; GAPDH-R, 5=-GGTGCTAAGCAGTTGGTGGT-3=; PKR-F, 5=-GCTGAGCACAGGGCTAGAAG-3=; PKR-R, 5=-A ACACCCTGGCATATAGTTGGA-3=; ISG15-F, 5=-GCGAACTC ATCTTTGCCAGTA-3=; ISG15-R, 5=-AGCATCTTCACCGTCA GGTC-3=.…”

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Abrogation of the Interferon Response Promotes More Efficient Human Cytomegalovirus Replication

McSharry

Forbes

Avdic

et al. 2015

J Virol

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dThe effect of abrogating the interferon (IFN) response on human cytomegalovirus (HCMV) replication was investigated using primary human cells engineered to block either the production of or the response to type I IFNs. In IFN-deficient cells, HCMV produced larger plaques and spread and replicated more rapidly than in parental cells. These cells demonstrate the vital role of IFNs in controlling HCMV replication and provide useful tools to investigate the IFN response to HCMV. T ype I interferons (IFNs) play a crucial role in the control of viral infection through inducing expression of a suite of interferon-stimulated genes (ISGs), with many of these ISGs exhibiting direct antiviral activity that serves to control viral replication (1, 2). IFNs can also act indirectly in the antiviral response by promoting the activation and proliferation of innate and adaptive immune effectors, including natural killer cells, dendritic cells, and T and B cells (3, 4). Human cytomegalovirus (HCMV) is a large double-stranded DNA (dsDNA) virus that is an important pathogen associated with severe morbidity and mortality in the immunosuppressed, especially in the allogeneic hematopoietic stem cell transplant (HSCT) setting (5). HCMV is also the leading infectious cause of birth defects in the developed world (6).The importance of the IFN response in controlling cytomegalovirus infection is exemplified by the hypersensitivity of engineered mice with defects in the IFN response to murine cytomegalovirus (MCMV) replication and disease (7,8). Although CMV encodes a number of gene functions that modulate the IFN response by inhibiting both the production of and response to IFNs (9-17), HCMV infection is still capable of inducing IFN-␤, via an interferon regulatory factor 3 (IRF3)-dependent pathway, in human fibroblasts (HF) (9,15,(18)(19)(20)(21)(22)(23)(24)(25). Furthermore, treatment with exogenous type I and type II IFNs is known to restrict HCMV infection/replication in vitro and in vivo (9,12,(26)(27)(28), confirming the sensitivity of HCMV to IFN-mediated control. Despite a number of reports investigating the IFN response to HCMV, the effect of abrogating the IFN response on HCMV infection and replication, to our knowledge, has not previously been investigated and was studied here using engineered cell lines.Generation of IFN-deficient cell lines. To investigate the effect of abrogating the IFN response on HCMV replication, the known abilities of the nPro protein of bovine viral diarrhea virus (BVDV) to target IRF3 (blocking IFN-␤ production) (29) and of the V protein of parainfluenza virus type 5 (PIV-5) to target STAT1 (blocking IFN responsiveness) (30, 31) were utilized. Lentivirus vectors expressing the nPro and V genes, respectively, were generated as described previously (29). Primary HF from the ATCC (HFF-1) were transduced with the lentiviruses, and cells were selected using 1 g/ml puromycin. To test whether nPro/HF could produce IFN-␤ in response to HCMV infection, parental HF and nPro/HF were infected with HCMV strain Mer...

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Human Cytomegalovirus Upregulates Expression of the Lectin Galectin 9 via Induction of Beta Interferon

Cited by 20 publications

References 28 publications

Acute stimulation generates Tim‐3‐expressing T helper type 1 CD4 T cells that persist in vivo and show enhanced effector function

Acute stimulation generates Tim‐3‐expressing T helper type 1 CD4 T cells that persist in vivo and show enhanced effector function

Interferon-Independent Innate Responses to Cytomegalovirus

Abrogation of the Interferon Response Promotes More Efficient Human Cytomegalovirus Replication

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