scholarly journals Alpha/Beta Interferon Protects Adult Mice from Fatal Sindbis Virus Infection and Is an Important Determinant of Cell and Tissue Tropism

2000 ◽  
Vol 74 (7) ◽  
pp. 3366-3378 ◽  
Author(s):  
Kate D. Ryman ◽  
William B. Klimstra ◽  
Khuong B. Nguyen ◽  
Christine A. Biron ◽  
Robert E. Johnston
Keyword(s):  
Virus Replication ◽  
Sindbis Virus ◽  
High Titer ◽  
Cell Types ◽  
Interleukin 12 ◽  
Tissue Tropism ◽  
Necrosis Factor Alpha ◽  
Beta Interferon ◽  
Alpha Beta

ABSTRACT Infection of adult 129 Sv/Ev mice with consensus Sindbis virus strain TR339 is subclinical due to an inherent restriction in early virus replication and viremic dissemination. By comparing the pathogenesis of TR339 in 129 Sv/Ev mice and alpha/beta interferon receptor null (IFN-α/βR−/−) mice, we have assessed the contribution of IFN-α/β in restricting virus replication and spread and in determining cell and tissue tropism. In adult 129 Sv/Ev mice, subcutaneous inoculation with 100 PFU of TR339 led to extremely low-level virus replication and viremia, with clearance under way by 96 h postinoculation (p.i.). In striking contrast, adult IFN-α/βR−/− mice inoculated subcutaneously with 100 PFU of TR339 succumbed to the infection within 84 h. By 24 h p.i. a high-titer serum viremia had seeded infectious virus systemically, coincident with the systemic induction of the proinflammatory cytokines interleukin-12 (IL-12) p40, IFN-γ, tumor necrosis factor alpha, and IL-6. Replicating virus was located in macrophage-dendritic cell (DC)-like cells at 24 h p.i. in the draining lymph node and in the splenic marginal zone. By 72 h p.i. virus replication was widespread in macrophage-DC-like cells in the spleen, liver, lung, thymus, and kidney and in fibroblast-connective tissue and periosteum, with sporadic neuroinvasion. IFN-α/β-mediated restriction of TR339 infection was mimicked in vitro in peritoneal exudate cells from 129 Sv/Ev versus IFN-α/βR−/− mice. Thus, IFN-α/β protects the normal adult host from viral infection by rapidly conferring an antiviral state on otherwise permissive cell types, both locally and systemically. Ablation of the IFN-α/β system alters the apparent cell and tissue tropism of the virus and renders macrophage-DC-lineage cells permissive to infection.

scholarly journals The CXC Chemokines Gamma Interferon (IFN-γ)-Inducible Protein 10 and Monokine Induced by IFN-γ Are Released during Severe Melioidosis

2000 ◽  
Vol 68 (7) ◽  
pp. 3888-3893 ◽  
Author(s):  
Fanny N. Lauw ◽  
Andrew J. H. Simpson ◽  
Jan M. Prins ◽  
Sander J. H. van Deventer ◽  
Wipada Chaowagul ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Host Defense ◽  
Cell Types ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Activated T Lymphocytes ◽  
Ifn Γ ◽  
Inducible Protein

ABSTRACT Gamma interferon (IFN-γ)-inducible protein 10 (IP-10) and monokine induced by IFN-γ (Mig) are related CXC chemokines which bind to the CXCR3 receptor and specifically target activated T lymphocytes and natural killer (NK) cells. The production of IP-10 and Mig by various cell types in vitro is strongly dependent on IFN-γ. To determine whether IP-10 and Mig are released during bacterial infection in humans, we measured plasma levels of IP-10 and Mig in patients with melioidosis, a severe gram-negative infection caused byBurkholderia pseudomallei. IP-10 and Mig were markedly elevated in patients with melioidosis on admission, particularly in blood culture-positive patients, and remained elevated during the 72-h study period. Levels of IP-10 and Mig showed a positive correlation with IFN-γ concentrations and also correlated with clinical outcome. In whole blood stimulated with heat-killed B. pseudomallei, neutralization of IFN-γ and tumor necrosis factor alpha (TNF-α) partly attenuated IP-10 and Mig release, while anti-interleukin-12 (IL-12) and anti-IL-18 had a synergistic effect. Stimulation with other bacteria or endotoxin also induced strong secretion of IP-10 and Mig. These data suggest that IP-10 and Mig are part of the innate immune response to bacterial infection. IP-10 and Mig may contribute to host defense in Th1-mediated host defense during infections by attracting CXCR3+ Th1 cells to the site of inflammation.

scholarly journals Cholera Toxin and Heat-Labile Enterotoxin Activate Human Monocyte-Derived Dendritic Cells and Dominantly Inhibit Cytokine Production through a Cyclic AMP-Dependent Pathway

2002 ◽  
Vol 70 (10) ◽  
pp. 5533-5539 ◽  
Author(s):  
Kenneth C. Bagley ◽  
Sayed F. Abdelwahab ◽  
Robert G. Tuskan ◽  
Timothy R. Fouts ◽  
George K. Lewis
Keyword(s):  
Dendritic Cells ◽  
Cyclic Amp ◽  
Cholera Toxin ◽  
Human Monocyte ◽  
Cell Types ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Heat Labile

ABSTRACT Cholera toxin (CT) and heat-labile enterotoxin (LT) are powerful mucosal adjuvants whose cellular targets and mechanism of action are unknown. There is emerging evidence that dendritic cells (DC) are one of the principal cell types that mediate the adjuvant effects of these toxins in vivo. Here we investigate the effects of CT and LT on the maturation of human monocyte-derived DC (MDDC) in vitro. We found that an enzymatically active A domain is necessary for both CT and LT to induce the maturation of MDDC and that this activation is strictly cyclic AMP (cAMP) dependent. ADP-ribosylation-defective derivatives of these toxins failed to induce maturation of MDDC, whereas dibutyryl-cyclic-3′,5′-AMP and Forskolin mimic the maturation of MDDC induced by CT and LT. In addition, an inhibitor of cAMP-dependent kinases, Rp-8-Br-cAMPs, blocked the ability of CT, LT, and Forskolin to activate MDDC. CT, LT, dibutyryl-cyclic-3′,5′-AMP, and Forskolin also dominantly inhibit interleukin 12 and tumor necrosis factor alpha production by MDDC in the presence of saturating concentrations of lipopolysaccharide. Taken together, these results show that the effects of CT and LT on MDDC are mediated by cAMP.

Metabolism of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine in Combination in Human Immunodeficiency Virus Infected Lymphoblastoid Cells

1992 ◽  
Vol 3 (3) ◽  
pp. 165-170 ◽  
Author(s):  
S. Cox
Keyword(s):  
Human Immunodeficiency Virus ◽  
Virus Replication ◽  
Cell Types ◽  
Human Immunodeficiency Virus Replication ◽  
Lymphoblastoid Cells ◽  
Synergistic Inhibition ◽  
Immunodeficiency Virus ◽  
Deoxynucleoside Triphosphate ◽  
The Individual

A combination of 3′-azido-3′-deoxythymidine (AZT) with 3′-fluoro-3′-deoxythymidine (FLT) has been shown previously to give synergistic inhibition of human immunodeficiency virus replication and greatly reduced cytotoxicity in vitro. The phosphorylation of the compounds, and their effect upon the natural deoxynucleoside triphosphate pools, were compared in CEM, H9, and HIV-infected H9 lymphoblastoid cells, both for the compounds when used alone and when combined together. Higher levels of FLT triphosphate than AZT triphosphate, and higher levels of AZT monophosphate than FLT monosphosphate, were formed in all cell types. Both compounds were phosphorylated most efficiently in CEM cells, whereas they were least efficiently phosphorylated in infected H9 cells. Owing to competition, the phosphorylation of both analogues was reduced when used in combination, compared to the phosphorylation of the separate compounds. The phosphorylation of the separate compounds was therefore at a maximum and was not increased by combining the compounds. The two compounds competed equally with each other for phosphorylation when used at a ratio of AZT: FLT of 5: 1. Both analogues severely reduced the deoxynucleoside triphosphate pools in uninfected and human immunodeficiency virus-infected H9 cells, but not in CEM cells. The effects of the two compounds were similar to those found when the compounds were combined, and thus H9 cells were shown to be much more sensitive to the effects of the analogues upon deoxynucleoside triphosphate pools than CEM cells were. Thus the synergistic combination of 3′-azido-3′-deoxythymidine and 3′-fluoro-3′-deoxythymidine was shown to have a similar metabolism and a similar effect upon cellular deoxynucleoside triphosphate pools to the individual compounds.

scholarly journals Toll-Like Receptor 2 Controls the Gamma Interferon Response to Francisella tularensis by Mouse Liver Lymphocytes

2007 ◽  
Vol 75 (11) ◽  
pp. 5338-5345 ◽  
Author(s):  
Kee-Jong Hong ◽  
Jason R. Wickstrum ◽  
Hung-Wen Yeh ◽  
Michael J. Parmely
Keyword(s):  
Francisella Tularensis ◽  
Cell Types ◽  
Gamma Interferon ◽  
Interferon Response ◽  
Interleukin 12 ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT The production of gamma interferon (IFN-γ) is a key step in the protective innate immune response to Francisella tularensis. Natural killer cells and T cells in the liver are important sources of this cytokine during primary F. tularensis infections, and interleukin-12 (IL-12) appears to be an essential coactivating cytokine for hepatic IFN-γ expression. The present study was undertaken to determine whether or not macrophages (Mφ) or dendritic cells (DC) provide coactivating signals for the liver IFN-γ response in vitro, whether IL-12 mediates these effects, and whether Toll-like receptor (TLR) signaling is essential to induce this costimulatory activity. Both bone marrow-derived Mφ and DC significantly augmented the IFN-γ response of F. tularensis-challenged liver lymphocytes in vitro. While both cell types produced IL-12p40 in response to F. tularensis challenge, only DC secreted large quantities of IL-12p70. DC from both IL-12p35-deficient and TLR2-deficient mice failed to produce IL-12p70 and did not costimulate liver lymphocytes for IFN-γ production in response to viable F. tularensis organisms. Conversely, liver lymphocytes from TLR2-deficient mice cocultured with wild-type accessory cells produced IFN-γ at levels comparable to those for wild-type hepatic lymphocytes. These findings indicate that TLR2 controls hepatic lymphocyte IFN-γ responses to F. tularensis by regulating DC IL-12 production. While Mφ also coinduced hepatic IFN-γ production in response to F. tularensis, they did so in a fashion less dependent on TLR2.

scholarly journals Alpha/Beta Interferon Inhibits Cap-Dependent Translation of Viral but Not Cellular mRNA by a PKR-Independent Mechanism

2007 ◽  
Vol 82 (6) ◽  
pp. 2620-2630 ◽  
Author(s):  
Mulu Z. Tesfay ◽  
Jun Yin ◽  
Christina L. Gardner ◽  
Mikhail V. Khoretonenko ◽  
Nadejda L. Korneeva ◽  
...  
Keyword(s):  
Sindbis Virus ◽  
Antiviral Effect ◽  
Protein Accumulation ◽  
Rnase L ◽  
80S Ribosome ◽  
Host Protection ◽  
Beta Interferon ◽  
Genes Encoding ◽  
Alpha Beta ◽  
Antiviral Proteins

ABSTRACT The alpha/beta interferon (IFN-α/β) response is critical for host protection against disseminated replication of many viruses, primarily due to the transcriptional upregulation of genes encoding antiviral proteins. Previously, we determined that infection of mice with Sindbis virus (SB) could be converted from asymptomatic to rapidly fatal by elimination of this response (K. D. Ryman et al., J. Virol. 74:3366-3378, 2000). Probing of the specific antiviral proteins important for IFN-mediated control of virus replication indicated that the double-stranded RNA-dependent protein kinase, PKR, exerted some early antiviral effects prior to IFN-α/β signaling; however, the ability of IFN-α/β to inhibit SB and protect mice from clinical disease was essentially undiminished in the absence of PKR, RNase L, and Mx proteins (K. D. Ryman et al., Viral Immunol. 15:53-76, 2002). One characteristic of the PKR/RNase L/Mx-independent antiviral effect was a blockage of viral protein accumulation early after infection (K. D. Ryman et al., J. Virol. 79:1487-1499, 2005). We show here that IFN-α/β priming induces a PKR-independent activity that inhibits m7G cap-dependent translation at a step after association of cap-binding factors and the small ribosome subunit but before formation of the 80S ribosome. Furthermore, the activity targets mRNAs that enter across the cytoplasmic membrane, but nucleus-transcribed RNAs are relatively unaffected. Therefore, this IFN-α/β-induced antiviral activity represents a mechanism through which IFN-α/β-exposed cells are defended against viruses that enter the cytoplasm, while preserving essential host activities, including the expression of antiviral and stress-responsive genes.

scholarly journals Effects of inducing or inhibiting apoptosis on Sindbis virus replication in mosquito cells

2008 ◽  
Vol 89 (11) ◽  
pp. 2651-2661 ◽  
Author(s):  
Hua Wang ◽  
Carol D. Blair ◽  
Ken E. Olson ◽  
Rollie J. Clem
Keyword(s):  
Virus Replication ◽  
Persistent Infection ◽  
Sindbis Virus ◽  
Actinomycin D ◽  
Virus Production ◽  
Cell Types ◽  
Lytic Infection ◽  
Mosquito Cells ◽  
Infected Cells ◽  
Apoptotic Genes

Sindbis virus (SINV) is a mosquito-borne virus in the genus Alphavirus, family Togaviridae. Like most alphaviruses, SINVs exhibit lytic infection (apoptosis) in many mammalian cell types, but are generally thought to cause persistent infection with only moderate cytopathic effects in mosquito cells. However, there have been several reports of apoptotic-like cell death in mosquitoes infected with alphaviruses or flaviviruses. Given that apoptosis has been shown to be an antiviral response in other systems, we have constructed recombinant SINVs that express either pro-apoptotic or anti-apoptotic genes in order to test the effects of inducing or inhibiting apoptosis on SINV replication in mosquito cells. Recombinant SINVs expressing the pro-apoptotic genes reaper (rpr) from Drosophila or michelob_x (mx) from Aedes aegypti caused extensive apoptosis in cells from the mosquito cell line C6/36, thus changing the normal persistent infection observed with SINV to a lytic infection. Although the infected cells underwent apoptosis, high levels of virus replication were still observed during the initial infection. However, virus production subsequently decreased compared with persistently infected cells, which continued to produce high levels of virus over the next several days. Infection of C6/36 cells with SINV expressing the baculovirus caspase inhibitor P35 inhibited actinomycin D-induced caspase activity and protected infected cells from actinomycin D-induced apoptosis, but had no observable effect on virus replication. This study is the first to test directly whether inducing or inhibiting apoptosis affects arbovirus replication in mosquito cells.

scholarly journals In vitro differentiation of CD34+ hematopoietic progenitor cells toward distinct dendritic cell subsets of the birbeck granule and MIIC- positive Langerhans cell and the interdigitating dendritic cell type

Blood ◽  
1996 ◽  
Vol 88 (7) ◽  
pp. 2541-2548 ◽  
Author(s):  
B Herbst ◽  
G Kohler ◽  
A Mackensen ◽  
H Veelken ◽  
P Kulmburg ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Progenitor Cells ◽  
Mhc Class Ii ◽  
Cell Function ◽  
Fluorescein Isothiocyanate ◽  
Cell Types ◽  
Birbeck Granule ◽  
Hematopoietic Growth Factors ◽  
Necrosis Factor Alpha

We have demonstrated recently that Birbeck granule-positive Langerhans cells (LC) can be derived from CD34+ peripheral blood progenitor cells in the presence of a seven-cytokine cocktail (CC7–7). Here, we show that the sequential use of early-acting hematopoietic growth factors, stem cell factor, interleukin (IL)-3, and IL-6, followed on day 8 by differentiation in the two-factor combination IL-4 plus granulocytemacrophage colony-stimulating factor (GM-CSF) (CC4GM) is more efficient and allows the cells to be arrested in the LC stage for more than 1 week while continuous maturation occurs in CC7–7. Maturation of LC to interdigitating dendritic cells (DC) could specifically be induced within 60 hours by addition of tumor necrosis factor-alpha (20 ng/mL) or lipopolysaccharide (100 ng/mL). Using LC that had been enriched to greater than 90% CD1a+ cells by an immunoaffinity column, we were able to define clear-cut differences between LC and DC that corroborate data of the respective cells derived from epithelial borders (LC) or from lymph nodes (LN) and spleen (DC). Thus, molecules and functions involved in antigen (AG) uptake and processing were highly expressed in LC, while those involved in AG presentation were at maximum in DC. LC were CD1a+2 DR+2, CD23+, CD36+, CD80-, CD86-, and CD25-, while DC were CD1a+/- DR+3, CD23-, CD36-, CD80+, CD86+2, and CD25+, CD40 and CD32 were moderately expressed and nearly unchanged on maturation, in contrast to monocyte-derived DC. Macropinocytosis of fluorescein isothiocyanate-dextran was dominant in LC, as were multilamellar major histocompatibility complex (MHC) class II compartments (MIICs), which were detected by electron microscopy. The functional dichotomy of these cell types was finally supported by testing the AG-presenting cell function for tetanus toxoid to primed autologous T-cell lines, which was optimal when cells were loaded with AG as LC and subsequently induced to become DC.

scholarly journals Interleukin 12, interferon gamma, and tumor necrosis factor alpha are the key cytokines of the generalized Shwartzman reaction.

1994 ◽  
Vol 180 (3) ◽  
pp. 907-915 ◽  
Author(s):  
L Ozmen ◽  
M Pericin ◽  
J Hakimi ◽  
R A Chizzonite ◽  
M Wysocka ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Cell Types ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Ifn Gamma ◽  
Lps Challenge ◽  
Mortality Incidence ◽  
Shwartzman Reaction ◽  
Lethal Reaction ◽  
The Individual

The Shwartzman reaction is elicited by two injections of lipopolysaccharide (LPS) in mice. The priming LPS injection is given in the footpad, whereas the lethal LPS challenge is given intravenously 24 h later. The injection of interferon gamma (IFN-gamma) or interleukin 12 (IL-12) instead of the LPS priming injection induced the lethal reaction in mice further challenged with LPS. Antibodies against IFN-gamma when given together with the priming agent, prevented the lethal reaction in mice primed with either LPS, IL-12, or IFN-gamma. Antibodies against IL-12, when given together with the priming agent, prevented the lethal reaction in mice primed with either LPS or IL-12 but not with IFN-gamma. These results strongly suggest that LPS induces the release of IL-12, that IL-12 induces the production of IFN-gamma, and that IFN-gamma is the cytokine that primes macrophages and other cell types. Upon LPS challenge, the lethal Shwartzman reaction is induced by a massive production of inflammatory cytokines that act on the target sites already sensitized by IFN-gamma. If mixtures of TNF and IL-1 or mixtures of TNF and IFN-gamma are used to challenge mice previously primed with IFN-gamma or IL-12, mortality is induced. In the same conditions, the individual cytokines or a mixture of IL-1 and IFN-gamma do not replace the LPS challenge. When the mice are primed with LPS, the combination of TNF, IL-1, and IFN-gamma induced only a partial mortality incidence suggesting that the involvement of other LPS-induced factors.

scholarly journals HSP27 Is a Ubiquitin-Binding Protein Involved in I-κBα Proteasomal Degradation

2003 ◽  
Vol 23 (16) ◽  
pp. 5790-5802 ◽  
Author(s):  
Arnaud Parcellier ◽  
Elise Schmitt ◽  
Sandeep Gurbuxani ◽  
Daphné Seigneurin-Berny ◽  
Alena Pance ◽  
...  
Keyword(s):  
Direct Interaction ◽  
Cell Types ◽  
26S Proteasome ◽  
Necrosis Factor Alpha ◽  
Polyubiquitin Chains ◽  
Ubiquitinated Proteins ◽  
Activation Of Transcription ◽  
Ubiquitin Proteasome

ABSTRACT HSP27 is an ATP-independent chaperone that confers protection against apoptosis through various mechanisms, including a direct interaction with cytochrome c. Here we show that HSP27 overexpression in various cell types enhances the degradation of ubiquitinated proteins by the 26S proteasome in response to stressful stimuli, such as etoposide or tumor necrosis factor alpha (TNF-α). We demonstrate that HSP27 binds to polyubiquitin chains and to the 26S proteasome in vitro and in vivo. The ubiquitin-proteasome pathway is involved in the activation of transcription factor NF-κB by degrading its main inhibitor, I-κBα. HSP27 overexpression increases NF-κB nuclear relocalization, DNA binding, and transcriptional activity induced by etoposide, ΤNF-α, and interleukin 1β. HSP27 does not affect I-κBα phosphorylation but enhances the degradation of phosphorylated I-κBα by the proteasome. The interaction of HSP27 with the 26S proteasome is required to activate the proteasome and the degradation of phosphorylated I-κBα. A protein complex that includes HSP27, phosphorylated I-κBα, and the 26S proteasome is formed. Based on these observations, we propose that HSP27, under stress conditions, favors the degradation of ubiquitinated proteins, such as phosphorylated I-κBα. This novel function of HSP27 would account for its antiapoptotic properties through the enhancement of NF-κB activity.

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