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Increased T-bet+ cytotoxic effectors and type I interferon–mediated processes in chronic graft-versus-host disease of the oral mucosa

Imanguli, Matin M.; Swaim, William D.; League, Stacy C.; Gress, Ronald E.; Pavletic, Steven Z.; Hakim, Frances T.
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 09/04/2009 EN
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Although chronic graft-versus-host disease (cGVHD) is a major long-term complication of allogeneic hematopoietic stem cell transplantation, little is known of its pathogenesis. We have systematically examined oral mucosa among cGVHD patients and determined that the clinical severity of oral cGVHD was correlated with apoptotic epithelial cells, often found adjacent to infiltrating effector-memory T cells expressing markers of cytotoxicity and type I cytokine polarization. Accumulation of T-bet+ T-cell effectors was associated with both increased proliferation and the expression of the type I chemokine receptor CXCR3. Concurrently, in both infiltrating cells and keratinocytes, we observed increased expression of the CXCR3 ligand MIG (CXCL9) and interleukin-15 (IL-15), type I interferon (IFN)–inducible factors that support the migration, type I differentiation, and expansion of alloreactive effectors. In severely affected mucosa, we observed high levels of MxA, a protein specifically induced by type I IFN, and signal transducer and activator of transcription 1 (STAT1) phosphorylation, a critical step in the IFN-signaling pathway, along with increased numbers of plasmacytoid dendritic cells. These data challenge the current paradigm of cGVHD as a type II cytokine–driven disorder and support the model that oral cGVHD results from type I IFN–driven immigration...

Desensitization to type I interferon in HIV-1 infection correlates with markers of immune activation and disease progression

Hardy, Gareth A. D.; Sieg, Scott F.; Rodriguez, Benigno; Jiang, Wei; Asaad, Robert; Lederman, Michael M.; Harding, Clifford V.
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 28/05/2009 EN
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Type I interferon (IFNα/β) plays a complex role in HIV-1 infection and has been proposed alternately to have roles in either disease protection or progression. Although IFNα/β plays crucial roles in regulating monocytes and dendritic cells, responsiveness of these cells to IFNα/β in HIV-1 infection is poorly understood. We report significant defects in IFNα/β receptor (IFNα/βR) expression, IFNα signaling, and IFNα-induced gene expression in monocytes from HIV-1–infected subjects. IFNα/βR expression correlated directly with CD4+ T-cell count and inversely with HIV-1 RNA level and expression of CD38 by memory (CD45RO+) CD8+ T cells, a measure of pathologic immune activation in HIV-1 infection associated with disease progression. In addition, monocytes from HIV-1–infected persons showed diminished responses to IFNα, including decreased induction of phosphorylated STAT1 and the classical interferon-stimulated gene produces MxA and OAS. These IFNα responses were decreased regardless of IFNα/βR expression, suggesting that regulation of intracellular signaling may contribute to unresponsiveness to IFNα/β in HIV-1 disease. Defective monocyte responses to IFNα/β may play an important role in the pathogenesis of HIV-1 infection...

Major Depletion of Plasmacytoid Dendritic Cells in HIV-2 Infection, an Attenuated Form of HIV Disease

Cavaleiro, Rita; Baptista, António P.; Soares, Rui S.; Tendeiro, Rita; Foxall, Russell B.; Gomes, Perpétua; Victorino, Rui M. M.; Sousa, Ana E.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN
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Plasmacytoid dendritic cells (pDC) provide an important link between innate and acquired immunity, mediating their action mainly through IFN-α production. pDC suppress HIV-1 replication, but there is increasing evidence suggesting they may also contribute to the increased levels of cell apoptosis and pan-immune activation associated with disease progression. Although having the same clinical spectrum, HIV-2 infection is characterized by a strikingly lower viremia and a much slower rate of CD4 decline and AIDS progression than HIV-1, irrespective of disease stage. We report here a similar marked reduction in circulating pDC levels in untreated HIV-1 and HIV-2 infections in association with CD4 depletion and T cell activation, in spite of the undetectable viremia found in the majority of HIV-2 patients. Moreover, the same overexpression of CD86 and PD-L1 on circulating pDC was found in both infections irrespective of disease stage or viremia status. Our observation that pDC depletion occurs in HIV-2 infected patients with undetectable viremia indicates that mechanisms other than direct viral infection determine the pDC depletion during persistent infections. However, viremia was associated with an impairment of IFN-α production on a per pDC basis upon TLR9 stimulation. These data support the possibility that diminished function in vitro may relate to prior activation by HIV virions in vivo...

Coordinated Regulation of SIV Replication and Immune Responses in the CNS

Witwer, Kenneth W.; Gama, Lucio; Li, Ming; Bartizal, Christopher M.; Queen, Suzanne E.; Varrone, John J.; Brice, Angela K.; Graham, David R.; Tarwater, Patrick M.; Mankowski, Joseph L.; Zink, M. Christine; Clements, Janice E.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 17/12/2009 EN
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Central nervous system (CNS) invasion during acute-stage HIV-infection has been demonstrated in a small number of individuals, but there is no evidence of neurological impairment at this stage and virus infection in brain appears to be controlled until late-stage disease. Using our reproducible SIV macaque model to examine the earliest stages of infection in the CNS, we identified immune responses that differentially regulate inflammation and virus replication in the brain compared to the peripheral blood and lymphoid tissues. SIV replication in brain macrophages and in brain of SIV-infected macaques was detected at 4 days post-inoculation (p.i.). This was accompanied by upregulation of innate immune responses, including IFNβ, IFNβ-induced gene MxA mRNA, and TNFα. Additionally, IL-10, the chemokine CCL2, and activation markers in macrophages, endothelial cells, and astrocytes were all increased in the brain at four days p.i. We observed synchronous control of virus replication, cytokine mRNA levels and inflammatory markers (MHC Class II, CD68 and GFAP) by 14 days p.i.; however, control failure was followed by development of CNS lesions in the brain. SIV infection was accompanied by induction of the dominant-negative isoform of C/EBPβ...

The Clinically Approved Proteasome Inhibitor PS-341 Efficiently Blocks Influenza A Virus and Vesicular Stomatitis Virus Propagation by Establishing an Antiviral State▿ †

Dudek, Sabine Eva; Luig, Christina; Pauli, Eva-Katharina; Schubert, Ulrich; Ludwig, Stephan
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
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Recently it has been shown that the proinflammatory NF-κB pathway promotes efficient influenza virus propagation. Based on these findings, it was suggested that NF-κB blockade may be a promising approach for antiviral intervention. The classical virus-induced activation of the NF-κB pathway requires proteasomal degradation of the inhibitor of NF-κB, IκB. Therefore, we hypothesized that inhibition of proteasomal IκB degradation should impair influenza A virus (IAV) replication. We chose the specific proteasome inhibitor PS-341, which is a clinically approved anticancer drug also known as Bortezomib or Velcade. As expected, PS-341 treatment of infected A549 cells in a concentration range that was not toxic resulted in a significant reduction of progeny virus titers. However, we could not observe the proposed suppression of NF-κB-signaling in vitro. Rather, PS-341 treatment resulted in an induction of IκB degradation and activation of NF-κB as well as the JNK/AP-1 pathway. This coincides with enhanced expression of antiviral genes, such as interleukin-6 and, most importantly, MxA, which is a strong interferon (IFN)-induced suppressor of influenza virus replication. This suggests that PS-341 may act as an antiviral agent via induction of the type I IFN response. Accordingly...

Antiviral immune responses in H5N1-infected human lung tissue and possible mechanisms underlying the hyperproduction of interferon-inducible protein IP-10

Thitithanyanont, Arunee; Engering, Anneke; Uiprasertkul, Monkol; Ekchariyawat, Peeraya; Wiboon-ut, Suwimon; Kraivong, Romchat; Limsalakpetch, Amporn; Kum-Arb, Utaiwan; Yongvanitchit, Kosol; Sa-Ard-Iam, Noppadol; Rukyen, Pimprapa; Mahanonda, Rangsini; Kawk
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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Information on the immune response against H5N1 within the lung is lacking. Here we describe the sustained antiviral immune responses, as indicated by the expression of MxA protein and IFN-α mRNA, in autopsy lung tissue from an H5N1-infected patient. H5N1 infection of primary bronchial/tracheal epithelial cells and lung microvascular endothelial cells induced IP-10, and also up-regulated the retinoic acid-inducible gene-I (RIG-I). Down-regulation of RIG-I gene expression decreased IP-10 response. Co-culturing of H5N1-infected pulmonary cells with TNF-α led to synergistically enhanced production of IP-10. In the absence of viral infection, TNF-α and IFN-α also synergistically enhanced IP-10 response. Methylprednisolone showed only a partial inhibitory effect on this chemokine response. Our findings strongly suggest that both the H5N1 virus and the locally produced antiviral cytokines; IFN-α and TNF-α may have an important role in inducing IP-10 hyperresponse, leading to inflammatory damage in infected lung.

Vitamin D Decreases RSV Induction of NF-κB-linked Chemokines and Cytokines in Airway Epithelium While Maintaining the Antiviral State

Hansdottir, Sif; Monick, Martha M.; Lovan, Nina; Powers, Linda; Gerke, Alicia; Hunninghake, Gary W.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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Epidemiological studies suggest that low vitamin D levels may increase the risk or severity of respiratory viral infections. In this study, we examined the effect of vitamin D on respiratory syncytial virus (RSV) infected human airway epithelial cells. Airway epithelium converts 25-hydroxyvitamin D3 (storage form) to 1,25-dihydroxyvitamin D3 (active form). Active vitamin D, generated locally in tissues, is important for the non-skeletal actions of vitamin D including its effects on immune responses. We found that vitamin D induces IκBα, a NF-κB inhibitor, in airway epithelium and decreases RSV induction of NF-κB driven genes like interferon-β and CXCL10. We also found that exposing airway epithelial cells to vitamin D reduced induction of interferon stimulated proteins with important antiviral activity, e.g., MxA and ISG15. In contrast to RSV-induced gene expression, vitamin D had no effect on interferon signaling and isolated interferon induced gene expression. Inhibiting NF-κB with an adenovirus vector that expressed a non-degradable form of IκBα mimicked the effects of vitamin D. When the vitamin D receptor was silenced with siRNA the vitamin D effects were abolished. Most importantly we found that, in spite of inducing IκBα...

Inhibitory Effect of a Triterpenoid Compound, with or without Alpha Interferon, on Hepatitis C Virus Infection▿†

Watanabe, Takako; Sakamoto, Naoya; Nakagawa, Mina; Kakinuma, Sei; Itsui, Yasuhiro; Nishimura-Sakurai, Yuki; Ueyama, Mayumi; Funaoka, Yusuke; Kitazume, Akiko; Nitta, Sayuri; Kiyohashi, Kei; Murakawa, Miyako; Azuma, Seishin; Tsuchiya, Kiichiro; Oooka, Shiny
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /06/2011 EN
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A lack of patient response to alpha interferon (α-IFN) plus ribavirin (RBV) treatment is a major problem in eliminating hepatitis C virus (HCV). We screened chemical libraries for compounds that enhanced cellular responses to α-IFN and identified a triterpenoid, toosendanin (TSN). Here, we studied the effects and mechanisms of action of TSN on HCV replication and its effect on α-IFN signaling. We treated HCV genotype 1b replicon-expressing cells and HCV-J6/JFH-infected cells with TSN, with or without α-IFN, and the level of HCV replication was quantified. To study the effects of TSN on α-IFN signaling, we detected components of the interferon-stimulated gene factor 3 (ISGF3), phosphorylated signal transducer and activator of transcription 1 (STAT1), and STAT2 by Western blotting analysis; expression levels of mRNA of interferon regulatory factor 9 using real-time reverse transcription-PCR (RT-PCR); and interferon-stimulated response element reporter activity and measured the expression levels of interferon-inducible genes for 2′,5′-oligoadenylate synthetase, MxA, protein kinase R, and p56 using real-time RT-PCR. TSN alone specifically inhibited expression of the HCV replicon (50% effective concentration = 20.6 nM, 50% cytotoxic concentration > 3 μM...

The C-Terminal 42 Residues of the Tula Virus Gn Protein Regulate Interferon Induction▿

Matthys, Valery; Gorbunova, Elena E.; Gavrilovskaya, Irina N.; Pepini, Timothy; Mackow, Erich R.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /05/2011 EN
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Hantaviruses primarily infect the endothelial cell lining of capillaries and cause two vascular permeability-based diseases. The ability of pathogenic hantaviruses to regulate the early induction of interferon determines whether hantaviruses replicate in endothelial cells. Tula virus (TULV) and Prospect Hill virus (PHV) are hantaviruses which infect human endothelial cells but fail to cause human disease. PHV is unable to inhibit early interferon (IFN) responses and fails to replicate within human endothelial cells. However, TULV replicates successfully in human endothelial cells, suggesting that TULV is capable of regulating cellular IFN responses. We observed a >300-fold reduction in the IFN-stimulated genes (ISGs) MxA and ISG56 following TULV versus PHV infection of endothelial cells 1 day postinfection. Similar to results with pathogenic hantaviruses, expressing the TULV Gn protein cytoplasmic tail (Gn-T) blocked RIG-I- and TBK1-directed transcription from IFN-stimulated response elements (ISREs) and IFN-β promoters (>90%) but not transcription directed by constitutively active IFN regulatory factor-3 (IRF3). In contrast, expressing the PHV Gn-T had no effect on TBK1-induced transcriptional responses. Analysis of Gn-T truncations demonstrated that the C-terminal 42 residues of the Gn-T (Gn-T-C42) from TULV...

Nrf2 Expression Modifies Influenza A Entry and Replication in Nasal Epithelial Cells

Kesic, Matthew J.; Simmons, Steven O.; Bauer, Rebecca; Jaspers, Ilona
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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Influenza infection is a major cause of morbidity and mortality worldwide, especially during pandemics outbreaks. Emerging data indicate that phase II antioxidant enzyme pathways could play a role in virus-associated inflammation and immune clearance. While Nrf2-dependent gene expression is known to modify inflammation, a mechanistic role in viral susceptibility and clearance has yet to be elucidated. Therefore, we utilized differentiated human nasal epithelial cells (NEC) and an enzymatic virus-like particle entry assay, to examine the role Nrf2-dependent gene expression has on viral entry and replication. Herein, lentiviral vectors that express Nrf2-specific short hairpin (sh)-RNA effectively decreased both Nrf2 mRNA and Nrf2 protein expression in transduced human NEC from healthy volunteers. Nrf2 knockdown correlated with a significant increase in influenza virus entry and replication. Conversely, supplementation with the potent Nrf2 activators sulforaphane (SFN) and epigallocatechin gallate (EGCG) significantly decreased viral entry and replication. The suppressive effects of EGCG on viral replication were abolished in cells with knocked down Nrf2 expression, suggesting a causal relationship between EGCG-induced activation of Nrf2 and ability to protect against viral infection. Interestingly...

Induction of Innate Immune Responses by SIV In Vivo and In Vitro: Differential Expression and Function of RIG-I and MDA5

Co, Juliene G.; Witwer, Kenneth W.; Gama, Lucio; Zink, M. Christine; Clements, Janice E.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Publicado em 01/10/2011 EN
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Interferon-β induction occurs during acute simian immunodeficiency virus (SIV) infection in the brain. We have examined expression and function of cytosolic RNA sensors, retinoic acid inducible gene I (RIG-I), and melanoma differentiation-associated protein 5 (MDA5), in vivo in the brain of our consistent, accelerated SIV-macaque model and in vitro in SIV-infected macaque macrophages to identify the pathway of type I interferon (IFN) induction. MDA5 messenger RNA (mRNA) and protein were expressed at higher levels in the brain than RIG-I, with protein expression correlating with the severity of disease from 42 until 84 days post-inoculation. The siRNA experiments reveal that mRNA expression of IFN-inducible gene MxA is dependent on MDA5, but not RIG-I. Finally, we demonstrate that SIV infection leads to the production of double-stranded RNA in vivo, which may act as the MDA5 ligand. We have shown for the first time to our knowledge the functional role of MDA5 in the innate immune response to SIV infection.

SIV/Macaque Model of HIV Infection in Cocaine Users: Minimal Effects of Cocaine on Behavior, Virus Replication, and CNS Inflammation

Weed, Michael; Adams, Robert J.; Hienz, Robert D.; Meulendyke, Kelly A.; Linde, Michael E.; Clements, Janice E.; Mankowski, Joseph L.; Zink, M. Christine
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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Studies of the effects of drugs of abuse on HIV immune status, disease progression, and neuroAIDS have produced conflicting data and have not definitively shown whether this combination promotes cognitive impairment or disease progression. Using a consistent SIV–macaque model, we investigated the effects of cocaine on behavior, virologic parameters, and CNS inflammation. Macaques received either vehicle or chronic administration of behaviorally active doses of cocaine (1.7 or 3.2 mg/kg/day). Chronic cocaine administration reduced CD8+ T cell counts during acute and late stage infection but had no effect on CD4+ T cell counts. Low-dose cocaine-treated animals had lower CSF vRNA levels late in infection, but cocaine did not alter plasma viral load or vRNA or protein in brain. There were no differences in CSF CCL-2 or interleukin (IL)-6 levels or severity of encephalitis in cocaine-treated as compared to vehicle-treated macaques. There were no differences in brain inflammation or neurodegeneration markers, as determined by interferon (IFN)-β, MxA, CCL2, IL-6, TNFα, IFNγ, and indolamine 2,3-deoxygenase mRNA levels. APP levels also were not altered. The executive function of inhibitory control was not impaired in cocaine-treated or control animals following SIV infection. However...

Induction of Interferon Pathways Mediates In Vivo Resistance to Oncolytic Adenovirus

Liikanen, Ilkka; Monsurrò, Vladia; Ahtiainen, Laura; Raki, Mari; Hakkarainen, Tanja; Diaconu, Iulia; Escutenaire, Sophie; Hemminki, Otto; Dias, João D; Cerullo, Vincenzo; Kanerva, Anna; Pesonen, Sari; Marzioni, Daniela; Colombatti, Marco; Hemminki, Akse
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
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Oncolytic adenoviruses are an emerging experimental approach for treatment of tumors refractory to available modalities. Although preclinical results have been promising, and clinical safety has been excellent, it is also apparent that tumors can become virus resistant. The resistance mechanisms acquired by advanced tumors against conventional therapies are increasingly well understood, which has allowed development of countermeasures. To study this in the context of oncolytic adenovirus, we developed two in vivo models of acquired resistance, where initially sensitive tumors eventually gain resistance and relapse. These models were used to investigate the phenomenon on RNA and protein levels using two types of analysis of microarray data, quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. Interferon (IFN) signaling pathways were found upregulated and Myxovirus resistance protein A (MxA) expression was identified as a marker correlating with resistance, while transplantation experiments suggested a role for tumor stroma in maintaining resistance. Furthermore, pathway analysis suggested potential therapeutic targets in oncolytic adenovirus-resistant cells. Improved understanding of the antiviral phenotype causing tumor recurrence is of key importance in order to improve treatment of advanced tumors with oncolytic adenoviruses. Given the similarities between mechanisms of action...

XoxF Is Required for Expression of Methanol Dehydrogenase in Methylobacterium extorquens AM1 ▿

Skovran, Elizabeth; Palmer, Alexander D.; Rountree, Austin M.; Good, Nathan M.; Lidstrom, Mary E.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /11/2011 EN
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In Gram-negative methylotrophic bacteria, the first step in methylotrophic growth is the oxidation of methanol to formaldehyde in the periplasm by methanol dehydrogenase. In most organisms studied to date, this enzyme consists of the MxaF and MxaI proteins, which make up the large and small subunits of this heterotetrameric enzyme. The Methylobacterium extorquens AM1 genome contains two homologs of MxaF, XoxF1 and XoxF2, which are ∼50% identical to MxaF and ∼90% identical to each other. It was previously reported that xoxF is not required for methanol growth in M. extorquens AM1, but here we show that when both xoxF homologs are absent, strains are unable to grow in methanol medium and lack methanol dehydrogenase activity. We demonstrate that these defects result from the loss of gene expression from the mxa promoter and suggest that XoxF is part of a complex regulatory cascade involving the 2-component systems MxcQE and MxbDM, which are required for the expression of the methanol dehydrogenase genes.

Basal Activation of Type I Interferons (Alpha2 and Beta) and 2′5′OAS Genes: Insights into Differential Expression Profiles of Interferon System Components in Systemic Sclerosis

de Oliveira, Danilo Bretas; Almeida, Gabriel Magno de Freitas; Guedes, Antônio Carlos Martins; Santos, Flávia Patrícia Sena Teixeira; Bonjardim, Claudio Antônio; Ferreira, Paulo César Peregrino; Kroon, Erna Geessien
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
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Objective. Systemic sclerosis (SSc) is a complex autoimmune disease in which interferons (IFNs) may play an essential role. We hypothesized that type I and III IFNs may be found in increased levels in patients and be responsible for SSc autoimmune status. Methods. Type I and III IFN and ISG basal expression profiles were measured by qPCR using RNA from PBMCs of patients and controls . Results. Type I IFNs are increased in SSc patients, while no induction of type III IFNs was detected. This induction cannot be related to IRF7, since no upregulation of this gene was seen on patients. Of the ISGs tested, 2′5′OAS levels were increased in patients, while 6–16 and MxA levels were not. Conclusions. While there is no indication of type III IFN induction, increased levels of type I IFNs may lead to abnormal regulation of ISGs that can be responsible for immune system alterations described for SSc.

Exogenous IFN-alpha Administration Reduces Influenza A Virus Replication in the Lower Respiratory Tract of Rhesus Macaques

Matzinger, Shannon R.; Carroll, Timothy D.; Fritts, Linda; McChesney, Michael B.; Miller, Christopher J.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 29/12/2011 EN
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To determine the role of innate immune responses in controlling influenza A virus replication, rhesus macaques (RM) were administered pegylated IFN-alpha prior to virus challenge. Systemic and mucosal pegylated IFN-alpha administration induced expression of the interferon-stimulated genes (ISG) MxA and OAS in the airways. RM treated with IFN-alpha 24 hours prior to influenza virus challenge had significantly lower peak vRNA levels in the trachea compared to untreated animals. In addition to blunting viral replication, IFN-alpha treatment minimized the weight loss and spike in body temperature after influenza infection of RM. These results confirm the importance of IFN-alpha induced innate immune responses in the rapid control of influenza A virus replication in primates.

Innate Sensing of Foamy Viruses by Human Hematopoietic Cells

Rua, Réjane; Lepelley, Alice; Gessain, Antoine; Schwartz, Olivier
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /01/2012 EN
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Foamy viruses (FV) are nonpathogenic retroviruses that have cospeciated with primates for millions of years. FV can be transmitted through severe bites from monkeys to humans. Viral loads remain generally low in infected humans, and no secondary transmission has been reported. Very little is known about the ability of FV to trigger an innate immune response in human cells. A few previous reports suggested that FV do not induce type I interferon (IFN) in nonhematopoietic cells. Here, we examined how human hematopoietic cells sense FV particles and FV-infected cells. We show that peripheral blood mononuclear cells (PBMCs), plasmacytoid dendritic cells (pDCs), and the pDC-like cell line Gen2.2 detect FV, produce high levels of type I IFN, and express the IFN-stimulated gene MxA. Fewer than 20 FV-infected cells are sufficient to trigger an IFN response. Both prototypic and primary viruses stimulated IFN release. Donor cells expressing a replication-defective virus, carrying a mutated reverse transcriptase, induced IFN production by target cells as potently as wild-type virus. In contrast, an FV strain with env deleted, which does not produce viral particles, was inactive. IFN production was blocked by an inhibitor of endosomal acidification (bafilomycin A1) and by an endosomal Toll-like receptor (TLR) antagonist (A151). Silencing experiments in Gen2.2 further demonstrated that TLR7 is involved in FV recognition. Therefore...

Plasmacytoid dendritic cells infiltrate the skin in positive tuberculin skin test indurations

Bond, Emily; Liang, Frank; Sandgren, Kerrie J; Smed-Sörensen, Anna; Bergman, Peter; Brighenti, Susanna; Adams, William C.; Betemariam, Senait Ashenafi; Rangaka, Molebogeng X; Lange, Christoph; Wilkinson, Robert J.; Andersson, Jan; Loré, Karin
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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Plasmacytoid dendritic cells (pDC) are rarely present in normal skin but have been shown to infiltrate lesions of infections or autoimmune disorders. Here, we report that several DC subsets including CD123+ BDCA-2/CD303+ pDC accumulate in the dermis in indurations induced by the tuberculin skin test (TST), used to screen immune sensitization by Mycobacterium tuberculosis. Although the purified protein derivate (PPD) used in the TST did not itself induce pDC recruitment or IFNα production, the positive skin reactions showed high expression of the IFNα inducible protein MxA. In contrast, the local immune response to PPD was associated with substantial cell death and high expression of the cationic antimicrobial peptide LL37, which together can provide a means for pDC activation and IFNα production. In vitro, pDC showed low uptake of PPD compared to CD11c+ and BDCA-3/CD141+ myeloid DC subsets. Furthermore, supernatants from pDC activated with LL37-DNA complexes reduced the high PPD uptake in myeloid DC as well as decreased their capacity to activate T cell proliferation. Infiltrating pDC in the TST reaction site may thus have a regulatory effect upon the antigen processing and presentation functions of surrounding potent myeloid DC subsets to limit potentially detrimental and excessive immune stimulation.

Covalent Protein Modification with ISG15 via a Conserved Cysteine in the Hinge Region

Bade, Veronika N.; Nickels, Jochen; Keusekotten, Kirstin; Praefcke, Gerrit J. K.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 05/06/2012 EN
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The ubiquitin-like protein ISG15 (interferon-stimulated gene of 15 kDa) is strongly induced by type I interferons and displays antiviral activity. As other ubiquitin-like proteins (Ubls), ISG15 is post-translationally conjugated to substrate proteins by an isopeptide bond between the C-terminal glycine of ISG15 and the side chains of lysine residues in the substrates (ISGylation). ISG15 consists of two ubiquitin-like domains that are separated by a hinge region. In many orthologs, this region contains a single highly reactive cysteine residue. Several hundred potential substrates for ISGylation have been identified but only a few of them have been rigorously verified. In order to investigate the modification of several ISG15 substrates, we have purified ISG15 conjugates from cell extracts by metal-chelate affinity purification and immunoprecipitations. We found that the levels of proteins modified by human ISG15 can be decreased by the addition of reducing agents. With the help of thiol blocking reagents, a mutational analysis and miRNA mediated knock-down of ISG15 expression, we revealed that this modification occurs in living cells via a disulphide bridge between the substrates and Cys78 in the hinge region of ISG15. While the ISG15 activating enzyme UBE1L is conjugated by ISG15 in the classical way...

SOCS1 regulates the IFN but not NFκB pathway in TLR-stimulated human monocytes and macrophages

Prêle, Cecilia M; Woodward, Eleanor A; Bisley, Jacqueline; Keith-Magee, April; Nicholson, Sandra E; Hart, Prue H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/12/2008 EN
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SOCS1 can regulate TLR-mediated signal transduction, yet mechanistic studies in murine macrophages have been confusing and contradictory. This study has used an adenoviral transfection system to determine the role of SOCS1 in the regulation of TNFα production by activated human monocytes. Monocytes were infected with AdV-SOCS1 or with an empty vector control, AdV-GFP, for 24 h prior to activation with the TLR4 ligand, LPS. SOCS1 did not regulate TNFα mRNA or protein production within the first two hours of TLR4 activation. However, SOCS1 suppressed the sustained production of TNFα by primary human monocytes and synovial fluid macrophages ex vivo. In addition, SOCS1 regulated the production of IL-6, but not IL-10, by monocytes. Analysis of the early signaling pathway downstream of TLR4 demonstrated that SOCS1 had no regulatory effect on the activation or on the DNA binding capacity of NFκB. The late effects of LPS are mediated in part through the MyD88-independent pathway activating IRF3 and initiating the production of IFNβ. In response to adenoviral infection and prior to LPS exposure, monocytes expressed enhanced levels of IFNβ and Myxovirus A (MxA) mRNA, an anti-viral molecule characterizing IFNβ activity. These two genes were reduced in AdV-SOCS1-infected cells. Further...