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Results for “Type I interferon”

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PubMed1988

Epidermodysplasia verruciformis in a patient with Hodgkin's disease: characterization of a new papillomavirus type and interferon treatment.

A new human papillomavirus (HPV) was discovered in disseminated, macular, pityriasis versicolor-like lesions on the skin of the neck, face, scalp, and pubic region of a 42-year-old male suffering from Hodgkin's disease. Histopathology revealed features characteristic of epidermodysplasia verruciformis (ev). In contrast to classical ev, the lesions were almost exclusively seen in previously irradiated and UV-exposed skin areas. Papillomavirus capsid antigen was demonstrated with the genus-specific antiserum and the patient's serum, which had IgM and IgG antibody titers. HPV DNA was isolated from biopsies and cloned into the vector pIC20H. It proved to be related to ev-associated viruses, showing 23% cross-hybridization with DNA of the closest relative HPV14. The new HPV type was named HPV46. The genome was physically mapped and colinearly aligned with HPV8 DNA to establish its gene organization. Interferon treatment of the patient did not significantly change the clinical picture nor was the concentration of viral DNA per lesion affected. However, no virus capsid antigen was detectable after starting treatment.

Adult↗

PubMedDate not supplied

Type I interferons and the Th1/Th2 paradigm.

During the past year significant advances have been made in our understanding of the factors contributing to the differentiation of CD4+ T helper cell subsets. These have been driven, in part, by the realization that cytokines from the innate immune response, such as interleukin-12 (IL-12) and interferons (IFNs), play a critical role in T cell subset differentiation. This review covers some of the most recent data concerning the divergent role that IFNs have in the differentiation of human versus mouse T helper cell subsets. In this review we discuss the molecular basis for the specie-specific effect of type I IFN on the selective induction of Th1 type immune responses. Furthermore, since IFN-beta is used in the treatment of multiple sclerosis (MS) we discuss the potential effects of such treatment and the value of the Th1/Th2 paradigm in MS.

Animals↗

PubMed2006

The latent membrane protein 1 of Epstein-Barr virus (EBV) primes EBV latency cells for type I interferon production.

Epstein-Barr virus (EBV) latency has been associated with a variety of human cancers. Latent membrane protein 1 (LMP-1) is one of the key viral proteins required for transformation of primary B cells in vitro and establishment of EBV latency. We have previously shown that LMP-1 induces the expression of several interferon (IFN)-stimulated genes and has antiviral effect (Zhang, J., Das, S. C., Kotalik, C., Pattnaik, A. K., and Zhang, L. (2004) J. Biol. Chem. 279, 46335-46342). In this report, a novel mechanism related to the antiviral effect of LMP-1 is identified. We show that EBV type III latency cells, in which LMP-1 is expressed, are primed to produce robust levels of endogenous IFNs upon infection of Sendai virus. The priming action is due to the expression of LMP-1 but not EBV nuclear antigen 2 (EBNA-2). The signaling events from the C-terminal activator regions of LMP-1 are essential to prime cells for high IFN production. LMP-1-mediated activation of NF-kappaB is apparently necessary and sufficient for LMP-1-mediated priming effect in DG75 cells, a human B cell line. IFN regulatory factor 7 (IRF-7) that can be activated by LMP-1 is also implicated in the priming action. Taken together, these data strongly suggest that LMP-1 may prime EBV latency cells for IFN production and that the antiviral property of LMP-1 may be an intrinsic part of EBV latency program, which may assist the establishment and/or maintenance of viral latency.

Burkitt Lymphoma↗

PubMed2006

The S segment of Punta Toro virus (Bunyaviridae, Phlebovirus) is a major determinant of lethality in the Syrian hamster and codes for a type I interferon antagonist.

Two strains of Punta Toro virus (PTV), isolated from febrile humans in Panama, cause a differential pathogenesis in Syrian hamsters, which could be a useful model for understanding the virulence characteristics and differential outcomes in other phleboviral infections such as Rift Valley fever virus. Genetic reassortants produced between the lethal Adames (A/A/A) and nonlethal Balliet (B/B/B) strains were used in this study to investigate viral genetic determinants for pathogenesis and lethality in the hamster model. The S segment was revealed to be a critical genome segment, determining lethality with log(10) 50% lethal doses for each PTV genotype as follows (L/M/S convention): A/A/A, <0.7; B/A/A, <0.7; A/B/A, 1.5; B/B/A, 2.2; B/A/B, 4.7; A/B/B, >4.7; A/A/B, >4.7; B/B/B, >4.7. In addition, the Adames strain inhibits the induction of alpha/beta interferon (IFN-alpha/beta) in vivo and in vitro and inhibits the activation of the IFN-beta promoter. Expression of the PTV Adames NSs protein, encoded by the S RNA segment, inhibited the virus-mediated induction of an IFN-beta promoter-driven reporter gene, suggesting that PTV NSs functions as a type I IFN antagonist. Taken together, these data indicate a mechanism of pathogenesis in which the suppression of the type I IFN response early during PTV infection leads to early and uncontrolled viral replication and, ultimately, hamster death. This study contributes to our understanding of Phlebovirus pathogenesis and identifies potential targets for immune modulation to increase host survival.

Animals↗

PubMed1981

Interferon (type-alpha and gamma) production by fresh and cryopreserved human mononuclear cells. Brief report.

A comparative study of interferon (IFN) production (type-alpha and gamma) was carried out using Ficoll-hypaque purified fresh and cryopreserved mononuclear cells from eight normal healthy individuals. Newcastle disease virus-NDV (R2B strain) was used as an inducer for type-alpha and Staphylococcal enterotoxin-A-(SEA) for type-gamma IFN production. There was no significant difference between the titres of type-alpha and gamma-IFN and lymphocyte subpopulations of fresh and cryopreserved mononuclear cells studied under identical conditions.

Adult↗

PubMed1998

Type I interferon induces inhibitory 16-kD CCAAT/ enhancer binding protein (C/EBP)beta, repressing the HIV-1 long terminal repeat in macrophages: pulmonary tuberculosis alters C/EBP expression, enhancing HIV-1 replication.

We have previously observed that HIV-1 replication is suppressed in uninflamed lung and increased during tuberculosis. In vitro THP-1 cell-derived macrophages inhibited HIV-1 replication after infection with Mycobacterium tuberculosis. Suppression of HIV-1 replication was associated with inhibition of the HIV-1 long terminal repeat (LTR) and induction of ISGF-3, a type I interferon (IFN)-specific transcription factor. Repression of the HIV-1 LTR required intact CCAAT/enhancer binding protein (C/EBP) sites. THP-1 cell-derived macrophages infected with M. tuberculosis, lipopolysaccharide, or IFN-beta induced the 16-kD inhibitory C/EBPbeta isoform and coincidentally repressed HIV-1 LTR transcription. C/EBPbeta was the predominant C/EBP family member produced in THP-1 macrophages during HIV-1 LTR repression. In vivo, alveolar macrophages from uninflamed lung strongly expressed inhibitory 16-kD C/EBPbeta, but pulmonary tuberculosis abolished inhibitory C/EBPbeta expression and induced a novel C/EBP DNA binding protein. Therefore, in vitro, proinflammatory stimulation produces an IFN response inhibiting viral replication by induction of a C/EBPbeta transcriptional repressor. THP-1 cell-derived macrophages stimulated with type I IFN are similar to alveolar macrophages in the uninflamed lung in vivo. In contrast, the cellular immune response in active pulmonary tuberculosis disrupts this innate immunity, switching C/EBP expression and allowing high level viral replication.

Base Sequence↗

PubMed1993

Induction of SV40 early transcription by type I interferon.

Interferons (IFN) have cancer suppressor activities for many transformed cells; however, IFN does not suppress transformation by SV40 large T antigen. The studies described in this paper therefore evaluated the effect of IFN on SV40-promoted gene expression in 3T3T cells. The results show that SV40-promoted gene expression can be induced 200% or three-fold by Type I IFN treatment regardless of whether beta-galactosidase or chloramphenicol acetyltransferase (CAT) is used as the reporter gene. This IFN effect is dosage-dependent, requires 24-48 h of exposure for maximum induction of CAT activity, and is probably not due to a post-transcriptional effect of IFN on CAT because IFN has no effect on CAT expression driven by thymidine kinase promoter. The induction of SV40 early transcription by IFN does, however, require that the integration of plasmid within the cell's genome. Additional data specifically show that the SV40 promoter is required for IFN's effect because IFN will not induce CAT if the SV40 enhancer is inserted upstream of thymidine kinase promoter to control expression of CAT gene.

3T3 Cells↗

PubMed2005

Multiple sclerosis: interferon-beta induces CD123(+)BDCA2- dendritic cells that produce IL-6 and IL-10 and have no enhanced type I interferon production.

Interferon-beta (IFN-beta), an approved drug for multiple sclerosis (MS), acts on dendritic cells (DC) by suppressing IL-12p40 and increasing IL-10. This results in Th2-biased immune responses. The nature of IFN-beta-modulated DC remains elusive. Previously, we observed that IFN-beta dose dependently induces expression of CD123, i.e., a classical marker for plasmacytoid DC, on human blood monocyte-derived myeloid DC. Such IFN-beta-modulated DCs produce predominantly IL-10 but are IL-12 deficient, with potent Th2 promotion. In the present study, we further characterize IFN-beta-modulated DC by using recently identified blood DC antigens (BDCA), and investigate their ability to produce type I IFN in response to virus stimulation. We show that IFN-beta induces development of CD123+ DC from human blood monocytes, which coexpress BDCA4+ but are negative for BDCA2-, a specific marker for plasmacytoid DC. Such IFN-beta-modulated DC can produce IL-6 and IL-10 but not IL-12p40, and have no enhanced IFN-alpha and IFN-beta production. The findings indicate that IFN-beta-modulated DCs represent a myeloid DC subset with diminished CD11c, BDCA-1 and CD1a expression. They may promote Th2 and B cell differentiation through IL-6 and IL-10 production, and suppression of IL-12p40, but they have no enhanced antiviral capacity.

Adult↗

PubMed2005

Type I interferons trigger systemic, partial lymphocyte activation in response to viral infection.

The vast majority of both T and B cells in mice were found to up-regulate cell surface expression of the early activation markers CD69 and CD86, but not CD25, within 24 h of infection with Semliki Forest virus. Kinetics and magnitude of activation marker expression was dependent on live virus, dose, and correlated with strain virulence. Activation marker expression declined to baseline levels over the next 96 h. This very early "activation" of such a high percentage of lymphocytes required the presence of type I IFN receptor genes, was inducible with poly(I:C), and correlated with IFN-I levels in serum. We conclude that virus-induced IFN-I release systemically affects most of the hosts T and B cells by triggering them rapidly and independently of Ag-reactivity into a semiactivated state.

Alphavirus Infections↗

PubMed2006

Differential type I interferon activation and susceptibility of dendritic cell populations to porcine arterivirus.

Dendritic cells (DCs) play a role in anti-viral immunity by providing early innate protection against viral replication and by presenting antigen to T cells for initiation of the adaptive immune response. Studies show the adaptive response to porcine reproductive and respiratory syndrome virus (PRRSV) is ineffective for complete viral elimination. Other studies describe the kinetics of the adaptive response to PRRSV, but have not investigated the early response by DCs. We hypothesize that there is an aberrant activation of DCs early in PRRSV infection; consequently, the adaptive response is triggered inadequately. The current study characterized a subtype of porcine lung DCs (L-DCs) and investigated the ability of PRRSV to infect and replicate in L-DCs and monocyte-derived DCs (MDDCs). Furthermore, the type I interferon anti-viral response to PRRSV with and without the addition of recombinant porcine IFN-alpha (rpIFN-alpha), an important cytokine that signals for anti-viral mediator activation, was analysed. Results show that PRRSV replicated in MDDCs but not L-DCs, providing evidence that these cells have followed distinct differentiation pathways. Although both cell types responded to PRRSV with an induction of IFN-beta mRNA, the magnitude and duration of the response differed between cell types. The addition of rpIFN-alpha was protective in MDDCs, and mRNA synthesis of Mx (myxovirus resistant) and PKR (double-stranded RNA dependent protein kinase) was observed in both cell types after rpIFN-alpha addition. Overall, PRRSV replicated in MDDCs but not L-DCs, and rpIFN-alpha was required for the transcription of protective anti-viral mediators. DC response to PRRSV was limited to IFN-beta transcription, which may be inadequate in triggering the adaptive immune response.

Animals↗

PubMed2004

Herpes simplex virus 2 virion host shutoff protein interferes with type I interferon production and responsiveness.

The herpes simplex virus 2 (HSV-2) virion host shutoff (vhs) protein is a ribonuclease contained in the virion tegument. vhs-deficient mutants of HSV-2 are profoundly attenuated in vivo, and we have previously shown that replication and virulence of vhs-deficient HSV-2 are largely restored to levels of wild-type virus in mice lacking the interferon alpha/beta receptor (IFNalphabetaR(-/-)). This result demonstrated that HSV-2 vhs interferes with the type I IFN response, but whether vhs inhibits production of type I IFN or synthesis or function of key mediators of the IFN-induced antiviral state was not clear. Here we address these questions using primary murine embryonic fibroblasts (MEFs), which produce and respond to IFNalphabeta. The vhs-deficient HSV-2 strain 333d41 replicated similarly to wild-type virus (333 clone SB5) and vhs rescue virus (333d41(R)) after infection of MEFs at high moi, but at low moi, 333d41 replication was severely attenuated, recapitulating the attenuated phenotype of vhs-deficient HSV-2 in vivo. Replication of 333d41 at low moi was restored to levels of wild-type virus in MEFs lacking the IFNalphabeta receptor or when IFNalphabeta was neutralized, thus establishing the IFNalphabeta response as the sole mechanism attenuating vhs-deficient HSV-2 replication in MEFs. MEFs infected with 333d41 produced >50-fold more IFNalphabeta than cells infected with 333 and 333d41(R). Pretreatment of MEFs with type I IFN inhibited replication of 333d41 more than 333 and 333d41(R), indicating that vhs also interferes with activation of the IFNalphabeta-induced antiviral response. We therefore examined vhs interference with PKR and RNase L, two key mediators of the IFNalphabeta response. 333d41 replication was restored to wild-type levels after low moi infection of PKR(-/-) and RNase L(-/-) MEFs, and was not inhibited in PKR(-/-) MEFs pretreated with IFNalpha. Together, these observations indicate that HSV-2 vhs is a broad and potent countermeasure to the IFN-mediated antiviral response in IFN-naïve and -sensitized MEFs.

Animals↗

PubMed2005

Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis.

The pathogenesis of primary biliary cirrhosis (PBC) remains enigmatic. In order to address this issue, we analyzed by laser capture microdissection and real-time reverse transcription-polymerase chain reaction the site-specific expression of messenger RNA (mRNA) for cytokines (interferon (IFN)-alpha, -beta, -gamma, interleukin (IL)-1beta, -4, -6, -10, -12p40, -18, tumor necrosis factor-alpha) and toll-like receptors (TLRs) (TLR-2, -3, -4, -7, -9) in portal tract and liver parenchyma from patients with early-stage PBC. Expression of IFN-alpha, -beta and TLR-3 proteins was also studied by immunohistochemistry. Autoimmune hepatitis (AIH) and chronic hepatitis C (CHC) served as disease controls. The expression levels of type I IFN (IFN-alpha, -beta) and TLR-3 mRNAs, which are known to induce type I IFN, were significantly higher in portal tract and liver parenchyma as compared to AIH and CHC. A strong positive correlation between the mRNA levels of type I IFN and TLR-3 was also seen in both areas. Immunohistologically, IFN-alpha is present in the mononuclear cells in portal tract and sinusoidal cells. Macrophages in portal tract and hepatocytes expressed IFN-beta and TLR-3. Furthermore, the level of IFN-alpha mRNA in the portal tract was positively correlated with serum alkaline phosphatase. In conclusion, these data indicate that TLR-3 and type I IFN signaling pathways are active in both the portal tract and liver parenchyma of early-stage PBC, and form the basis for our hypothesis that these signaling pathways are involved in the pathophysiology of PBC.

Aged↗

PubMed2006

A rapid and efficient method for generating anti-variable region monoclonal antibodies using type-1 interferons as immune modulators.

The generation of anti-variable region monoclonal antibodies (mAbs) against therapeutic antibodies is essential in the pharmacokinetic/pharmacodynamic (PK/PD) assessments of the drugs in clinical study samples. Sandwich EIA and other methods are typically employed to achieve sensitivity and selectivity for the PK/PD analyses. These assays usually require generation of mAb reagents that bind specifically to the drug in non-competing pair combinations. Thus, large panels of anti-variable region mAbs must be generated in an expeditious manner to increase the probability of success. Herein we describe a novel immunization method that utilizes type 1 interferons (IFNs) as immunomodulators coupled with an agonistic anti-CD40 mAb as a B cell proliferative agent to drive immune responses. This novel protocol allows for rapid and robust mAb reagent generation without the use of conventional protein-denaturing adjuvants. The use of IFNs allowed for the generation of comparable and in some cases, increased numbers of anti-variable region mAbs in a dramatically shorter timeframe. This IFN based, immunostimulatory approach utilizing a non-denaturing adjuvant, likely presents conformational epitopes and may optimize the humoral response for the rapid generation of anti-variable region reagents to therapeutic mAb candidates.

Adjuvants, Immunologic↗

PubMed2006

Global suppression of the host antiviral response by Ebola- and Marburgviruses: increased antagonism of the type I interferon response is associated with enhanced virulence.

We studied the effect of filovirus infection on host cell gene expression by characterizing the regulation of gene expression responses in human liver cells infected with Zaire Ebolavirus (ZEBOV), Reston Ebolavirus (REBOV), and Marburgvirus (MARV), using transcriptional profiling and bioinformatics. Expression microarray analysis demonstrated that filovirus infection resulted in the up-regulation of immune-related genes and the down-regulation of many coagulation and acute-phase proteins. These studies further revealed that a common feature of filovirus virulence is suppression of key cellular antiviral responses, including TLR-, interferon (IFN) regulatory factor 3-, and PKR-related pathways. We further showed that ZEBOV and MARV were more potent antagonists of the IFN response and inhibited the expression of most of the IFN-stimulated genes (ISGs) observed in mock-infected IFN-alpha-2b treated cells, compared to REBOV infection, which activated more than 20% of these ISGs. Finally, we examined IFN-related gene expression in filovirus-infected cells treated with IFN-alpha-2b. These experiments revealed that a majority of genes induced in mock-infected cells treated with type I IFN were antagonized in treated ZEBOV- and MARV-infected cells, while in contrast, REBOV infection resulted in a significant increase in ISG expression. Analysis of STAT1 and -2 phosphorylation following IFN treatment showed a significant reduction of STAT phosphorylation for MARV but not for ZEBOV and REBOV, indicating that different mechanisms might be involved in antagonizing IFN signaling pathways by the different filovirus species. Taken together, these studies showed a correlation between antagonism of type I IFN responses and filovirus virulence.

Animals↗

PubMed1985

Sensitivity of ortho- and paramyxovirus replication to human interferon alpha.

Replication of the influenza virus strains Influenza Ao/WSN (H0N1), fowl plague (Hav1N1) and B-Lee/40 (ATCC) and the paramyxovirus, New Castle disease virus (Victoria) are highly sensitive to human interferon type alpha in Madin Darby bovine kidney cells. Pretreatment of cells with human interferon type alpha resulted in protection of the cells against viral cytopathic effect. The inhibition of the orthomyxovirus strains used in this study and New Castle disease virus replication is mediated by an inhibition of viral protein synthesis. Residual WSN virus particles released from interferon treated cells showed the same structural protein pattern as virus particles isolated from control cells. Glycosylation of the viral structural components appeared to be unaffected by interferon.

Animals↗

PubMed1983

Effect of human interferon on type D retroviruses multiplication in chronically infected cell lines.

A study was made on the effect of human interferon (HuIFN) on the synthesis and release of type D viruses (MPMV and SMRV) by chronically infected human lines. Interferon at concentrations of 50 IU/ml lead to an inhibition of the extracellular virus production by about 50%-80% as measured by virus-associated reverse transcriptase activity, by metabolic labeling of the virus with (3H) uridine or (3H) amino acids, or by electron microscopy counting of particles. The profiles of intracellular viral proteins, as visualized by radioimmunoprecipitation and electrophoresis, were not different in control or IFN-treated cells and the yield of intracellular protein p27 stayed unchanged or was slightly increased. Electron microscopy of thin sections taken from the control and IFN-treated cells revealed no difference in any subcellular structures including that of the viruses. However, electron microscopic examination of IFN-treated cells showed an increased number of either budding particles and intracytoplasmic precursors (two- to five-fold) or mature virus particles (four- to ten-fold) on the cell surface of the IFN-treated cells. These results indicate that IFN inhibits further developments of MPMV and SMRV replication as was described for type C and B retroviruses.

Animals↗

PubMed2005

TICAM-1 and TICAM-2: toll-like receptor adapters that participate in induction of type 1 interferons.

Toll-like receptor (TLR) 3 and 4 mediate the expression of many genes, including NF-kappaB- and interferon-regulatory factor (IRF)-3/interferon (IFN)-inducible genes, in macrophages and dendritic cells (DCs) in response to their ligand stimuli, polyI:C and lipopolysaccharide (LPS). Toll-IL-1 receptor homology domain (TIR)-containing adapter molecule 1 (TICAM-1) facilitates expression of IFN-inducible genes via TLR3. Although MyD88 and Mal/TIRAP adapters function downstream of TLR4, they barely induce IFN-beta. In addition, DC maturation as well as IFN-beta induction are largely independent of MyD88 and Mal/TIRAP. TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. In LPS-mediated TLR4 activation, a complex of TICAM-1 and an additional TLR4-binding adapter serves as the adapter. We named this TLR4-TICAM-1-bridging adapter TICAM-2. Our results reveal the details of MyD88-independent pathways which separately recruit the distinct adapters downstream of TLR3 and TLR4 and variations of the TLR output are in part regulated by the two additional adapters in DCs.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Human type I interferons differ greatly in their effects on the proliferation of primary B cells.

We examined the effects of eight subtypes of human interferon-alpha (IFN-alpha) and human IFN-beta on primary human B cells. In costimulation with antibodies to IgM (but not to CD40), some of these induced the cells to proliferate (but not to differentiate). Individual IFN differed greatly in their relative proliferative effects. IFN-alpha8 at 0.1-0.5 ng/ml induced proliferation, whereas most other subtypes were active only at concentrations >5 ng/ml, and IFN-alpha1 was inactive. These marked differences were not due to a selective overall increase in B cell response only to some IFN subtypes, as all those tested similarly induced the IFN-inducible genes 6-16 and HLA class I. Our results show that human B cells must respond to type I IFN via two distinct pathways. One is specific for IFN-alpha8 but can be activated by other IFN at relatively high concentrations. The other responds to them all and causes activation of IFN-inducible genes.

B-Lymphocytes↗