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Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma.

ABSTRACT: Scleroderma (SSc) is a complex and heterogeneous connective tissue disease mainly characterized by autoimmunity, vascular damage, and fibrosis that mostly involve the skin and lungs. Epstein-Barr virus (EBV) is a lymphotropic γ-herpesvirus that has co-evolved with human species, infecting >95% of the adult population worldwide, and has been a leading candidate in triggering several autoimmune diseases. Here we show that EBV establishes infection in the majority of fibroblasts and endothelial cells in the skin of SSc patients, characterized by the expression of the EBV noncoding small RNAs (EBERs) and the increased expression of immediate-early lytic and latency mRNAs and proteins. We report that EBV is able to persistently infect human SSc fibroblasts in vitro, inducing an aberrant innate immune response in infected cells. EBV-Toll-like receptor (TLR) aberrant activation induces the expression of selected IFN-regulatory factors (IRFs), IFN-stimulated genes (ISGs), transforming growth factor-β1 (TGFβ1), and several markers of fibroblast activation, such as smooth muscle actin and Endothelin-1, and all of these genes play a key role in determining the profibrotic phenotype in SSc fibroblasts. These findings imply that EBV infection occurring in mesenchymal, endothelial, and immune cells of SSc patients may underlie the main pathological features of SSc including autoimmunity, vasculopathy, and fibrosis, and provide a unified disease mechanism represented by EBV reactivation.

SUBMITTER: Farina A

PROVIDER: S-EPMC3961515 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma.

Farina Antonella A Cirone Mara M York Michael M Lenna Stefania S Padilla Cristina C Mclaughlin Sarah S Faggioni Alberto A Lafyatis Robert R Trojanowska Maria M Farina Giuseppina A GA

The Journal of investigative dermatology 20131011 4

Scleroderma (SSc) is a complex and heterogeneous connective tissue disease mainly characterized by autoimmunity, vascular damage, and fibrosis that mostly involve the skin and lungs. Epstein-Barr virus (EBV) is a lymphotropic γ-herpesvirus that has co-evolved with human species, infecting >95% of the adult population worldwide, and has been a leading candidate in triggering several autoimmune diseases. Here we show that EBV establishes infection in the majority of fibroblasts and endothelial cel ...[more]

PMID: 24129067

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Project description:Background Interstitial and perivascular fibrosis may contribute to diabetes-associated heart failure. Pericytes can convert to fibroblasts under conditions of stress and have been implicated in the pathogenesis of fibrotic diseases. We hypothesized that in diabetic hearts, pericytes may convert to fibroblasts, contributing to fibrosis and to the development of diastolic dysfunction. Methods and Results Using pericyte:fibroblast dual reporter (NG2Dsred [neuron-glial antigen 2 red fluorescent protein variant]; PDGFRαEGFP [platelet-derived growth factor receptor alpha enhanced green fluorescent protein]) mice in a type 2 diabetic db/db background, we found that diabetes does not significantly affect pericyte density but reduces the myocardial pericyte:fibroblast ratio. Lineage tracing using the inducible NG2CreER driver, along with reliable labeling of fibroblasts with the PDGFRα reporter system, showed no significant pericyte to fibroblast conversion in lean and db/db hearts. In addition, db/db mouse cardiac fibroblasts did not undergo myofibroblast conversion and had no significant induction of structural collagens but exhibited a matrix-preserving phenotype, associated with increased expression of antiproteases, matricellular genes, matrix cross-linking enzymes, and the fibrogenic transcription factor cMyc. In contrast, db/db mouse cardiac pericytes had increased expression of Timp3, without any changes in expression of other fibrosis-associated genes. The matrix-preserving phenotype of diabetic fibroblasts was associated with induction of genes encoding oxidative (Ptgs2/cycloxygenase-2, and Fmo2) and antioxidant proteins (Hmox1, Sod1). In vitro, high glucose partially recapitulated the in vivo changes in diabetic fibroblasts. Conclusions Diabetic fibrosis is not mediated through pericyte to fibroblast conversion but involves acquisition of a matrix-preserving fibroblast program, which is independent of myofibroblast conversion and is only partially explained by the effects of the hyperglycemic environment.

Project description:We have discovered how Epstein-Barr virus (EBV) induces the reorganization of cellular chromatin (ROCC), in which host chromatin is compacted and marginated within the nucleus, with viral DNA replication occurring in the chromatin-free regions. Five families of DNA viruses induce ROCC: herpesviruses, adenoviruses, parvoviruses, baculoviruses, and geminiviruses. These families infect a variety of hosts, including vertebrates, insects, and plants. They also share several characteristics: they replicate and encapsidate their genomes in the host nucleus and package their genomes unbound by histones. We have identified the viral genes and processes required for EBV's ROCC. Each of EBV's seven core DNA synthesis genes and its origin of lytic replication (oriLyt), in trans, are required, while its protein kinase, BGLF4, and its true late genes are not. Following these findings, we tested the role of EBV lytic DNA amplification in driving ROCC. Surprisingly, the inhibition of EBV's lytic DNA synthesis still supports chromatin compaction but blocks its margination. We propose a two-step model for ROCC. First, the initiation of viral lytic DNA synthesis induces a cellular response that results in global chromatin compaction. Second, the histone-free, productive viral DNA synthesis leads to the margination of compacted chromatin to the nuclear periphery. We have tested this model by asking if the histone-associated simian virus 40 (SV40) DNA synthesis could substitute for oriLyt-mediated synthesis and found that EBV's ROCC is incompatible with SV40 DNA replication. Elucidating EBV's induction of ROCC both illuminates how other viruses can do so and indicates how this spatial control of cellular chromatin benefits them. IMPORTANCE Five families of viruses support the reorganization of cellular chromatin (ROCC), the compaction and margination of host chromatin, upon their productive infection. That they all share this phenotype implies the importance of ROCC in viral life cycles. With Epstein-Barr virus (EBV), a herpesvirus, we show that the viral replication complex and origin of lytic replication (oriLyt) are essential for ROCC. In contrast, its protein kinase and true late genes are not. We show that, unexpectedly, the viral lytic amplification is not required for chromatin compaction but is required for its margination. We propose a two-step model for ROCC: first, global chromatin compaction occurs as a cellular response to the initiation of viral DNA synthesis; then, the accumulation of newly synthesized, histone-free viral DNA leads to cellular chromatin margination. Taken together, our findings provide insights into a process contributing to the productive phase of five families of viruses.

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Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma.

Publications

Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma.

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