Hit-hit and hit-run: Viruses in the playing field of multiple sclerosis

Scarisbrick, Isobel A.; Rodriguez, Moses

doi:10.1007/s11910-003-0087-9

Cited by 40 publications

(38 citation statements)

References 54 publications

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“…This may also prove to be a more general phenomenon occurring during lifetime inflammatory events. Thus, quenching ERVK activity through antiretroviral or immunomodulatory regimens may hinder virus-mediated neuropathology and improve the symptoms of ALS or other ERVK-associated chronic diseases (52)(53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5′ Long Terminal Repeat

Manghera

Ferguson-Parry

Lin

et al. 2016

J Virol

113

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Thousands of endogenous retroviruses (ERV), viral fossils of ancient germ line infections, reside within the human genome. Evidence of ERV activity has been observed widely in both health and disease. While this is most often cited as a bystander effect of cell culture or disease states, it is unclear which signals control ERV transcription. Bioinformatic analysis suggests that the viral promoter of endogenous retrovirus K (ERVK) is responsive to inflammatory transcription factors. Here we show that one reason for ERVK upregulation in amyotrophic lateral sclerosis (ALS) is the presence of functional interferon-stimulated response elements (ISREs) in the viral promoter. Transcription factor overexpression assays revealed independent and synergistic upregulation of ERVK by interferon regulatory factor 1 (IRF1) and NF-B isoforms. Tumor necrosis factor alpha (TNF-␣) and LIGHT cytokine treatments of human astrocytes and neurons enhanced ERVK transcription and protein levels through IRF1 and NF-B binding to the ISREs. We further show that in ALS brain tissue, neuronal ERVK reactivation is associated with the nuclear translocation of IRF1 and NF-B isoforms p50 and p65. ERVK overexpression can cause motor neuron pathology in murine models. Our results implicate neuroinflammation as a key trigger of ERVK provirus reactivation in ALS. These molecular mechanisms may also extend to the pathobiology of other ERVK-associated inflammatory diseases, such as cancers, HIV infection, rheumatoid arthritis, and schizophrenia. IMPORTANCEIt has been well established that inflammatory signaling pathways in ALS converge at NF-B to promote neuronal damage. Our findings suggest that inflammation-driven IRF1 and NF-B activity promotes ERVK reactivation in neurons of the motor cortex in ALS. Thus, quenching ERVK activity through antiretroviral or immunomodulatory regimens may hinder virus-mediated neuropathology and improve the symptoms of ALS or other ERVK-associated diseases.T housands of endogenous retroviruses (ERV), viral fossils of ancient germ line infections, reside within the human genome. Evidence of ERV activity has been observed widely in both health and disease. While this is most often cited as a bystander effect of cell culture or disease states, it is unclear which signals control ERV transcription and whether their expression is relevant to cellular processes. We previously proposed that the viral promoter of endogenous retrovirus K (ERVK) is responsive to inflammatory transcription factors (1) due to the presence of two conserved interferon-stimulated response elements (ISREs). Thus, select proinflammatory transcription factors may drive ERVK expression.The transcription of integrated retroviral sequences within the human genome is regulated by viral promoters, called long terminal repeats (LTRs), flanking either side of the core viral genome. These LTRs contain transcriptional regulatory elements that are responsive to both viral and cellular transcription factors (TFs). Interferon regulatory factors (IRFs) and nu...

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Section: Discussionmentioning

confidence: 99%

NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5′ Long Terminal Repeat

Manghera

Ferguson-Parry

Lin

et al. 2016

J Virol

113

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“…31 The presence of plasmacytoid dendritic cells (pDCs) was assessed with 3 pDCs markers (BDCA-2, CD123, CD2ap); pDCs were not detected in active MS lesions in contrast to previous findings 32 (figure e-1B). Though the possible roles of viruses in the pathogenesis of MS have been discussed for many years, [33][34][35] there are conflicting recent reports on EBV infection in the MS brain. 6 -9 Our findings are in line with previous reports, which describe the presence of EBERϩ cells in the MS lesions 6 and the observation that active EBV infection is not a characteristic feature of the MS brain.…”

Section: Is Cerebral Expression Of Ebers Restricted To Ms?mentioning

confidence: 99%

Association of innate immune activation with latent Epstein-Barr virus in active MS lesions

Tzartos¹,

Khan²,

et al. 2012

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Objective: To determine whether the activation of innate immune responses, which can be elicited by pathogenic and endogenous triggers, is associated with the presence of Epstein-Barr virus (EBV) infection in the multiple sclerosis (MS) brain. Methods:White matter postmortem MS (n ϭ 10) and control tissue (n ϭ 11) was analyzed for the expression of the proinflammatory cytokine interferon ␣ (IFN␣) by immunohistochemistry and for EBV by using the highly sensitive method of EBV-encoded RNA (EBER) in situ hybridization. Results:We detected overexpression of IFN␣ in active areas of white matter MS lesions but not in inactive MS lesions, normal-appearing white matter, or normal brains. The presence of IFN␣ in macrophages and microglia (expressing human leukocyte antigen class II) is suggestive of local production as part of an acute inflammatory process. Interestingly, EBERs were also specifically detected in areas where IFN␣ was overexpressed in these preselected active MS lesions. EBERϩ cells were also found in CNS lymphoma and stroke cases, but were absent in other control brains. We next addressed a potential mechanism, e.g., the role of EBERs in eliciting IFN␣ production, and transfected EBERs into human embryonic kidney (HEK) cells. We used HEK cells that stably expressed Toll-like receptor-3, which recognizes double-stranded RNAs, associated with many viral infections. EBERs elicited IFN␣ production in vitro. Conclusion:These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, e.g., IFN␣ production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases. Neurology ® 2012;78:15-23 GLOSSARY ds ϭ double-stranded; EBER ϭ EBV-encoded RNA; EBNA-1 ϭ EBV nuclear antigen 1; EBV ϭ Epstein-Barr virus; FCS ϭ fetal calf serum; H&E ϭ hematoxylin & eosin; HEK ϭ human embryonic kidney; HLA ϭ human leukocyte antigen; HSE ϭ herpes simplex encephalitis; IFN␣ ϭ interferon ␣; IgG ϭ immunoglobulin G; ISH ϭ in situ hybridization; LFB ϭ Luxol fast blue; mAb ϭ monoclonal antibody; MS ϭ multiple sclerosis; OHL ϭ oral hairy leukoplakia; PBS ϭ phosphate-buffered saline; pDC ϭ plasmacytoid dendritic cell; PLP ϭ protein lipid protein; SLE ϭ systemic lupus erythematosus; SSPE ϭ subacute sclerosing panencephalitis; TLR3 ϭ Toll-like receptor-3.The innate immune response is an essential part of the host response to many infections and type I interferon (IFN) is produced within hours of systemic infection.1 Our previous findings showed that Toll-like receptor-3 (TLR3) stimulation of human microglia with the viral-mimic polyIC led to IFN␣ production and downstream Th1 polarization of CD4ϩ helper T cells, 2 which may impact on CNS immunity.

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“…85 The observation that lymphotropic viruses may selectively decrease SHP-1 expression lends support to the hypothesis that viral infection, possibly through epigenetic downmodulation of genes, can trigger immune-mediated demyelination. 86,87 Whether CpG methylation and/or histone deacetylation lead to stable epigenetic modification of promoter II in MS patients, is responsible for stable deficiency of SHP-1, and is responsible for increased CNS inflammation in MS lesions requires further investigation.…”

Section: Shp-1 Deficiency In Pbmcs Of Ms Patients Gp Christophi Et Almentioning

confidence: 99%

SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients

Christophi

Hudson

Gruber

et al. 2008

Laboratory Investigation

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Recent studies in mice have demonstrated that the protein tyrosine phosphatase SHP-1 is a crucial negative regulator of cytokine signaling, inflammatory gene expression, and demyelination in central nervous system. The present study investigates a possible similar role for SHP-1 in the human disease multiple sclerosis (MS). The levels of SHP-1 protein and mRNA in PBMCs of MS patients were significantly lower compared to normal subjects. Moreover, promoter II transcripts, expressed from one of two known promoters, were selectively deficient in MS patients. To examine functional consequences of the lower SHP-1 in PBMCs of MS patients, we measured the intracellular levels of phosphorylated STAT6 (pSTAT6). As expected, MS patients had significantly higher levels of pSTAT6. Accordingly, siRNA to SHP-1 effectively increased the levels of pSTAT6 in PBMCs of controls to levels equal to MS patients. Additionally, transduction of PBMCs with a lentiviral vector expressing SHP-1 lowered pSTAT6 levels. Finally, multiple STAT6-responsive inflammatory genes were increased in PBMCs of MS patients relative to PBMCs of normal subjects. Thus, PBMCs of MS patients display a stable deficiency of SHP-1 expression, heightened STAT6 phosphorylation, and an enhanced state of activation relevant to the mechanisms of inflammatory demyelination.

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Hit-hit and hit-run: Viruses in the playing field of multiple sclerosis

Cited by 40 publications

References 54 publications

NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5′ Long Terminal Repeat

NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5′ Long Terminal Repeat

Association of innate immune activation with latent Epstein-Barr virus in active MS lesions

SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients

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