scholarly journals The Roles of Chemokines in Rabies Virus Infection: Overexpression May Not Always Be Beneficial

2009 ◽  
Vol 83 (22) ◽  
pp. 11808-11818 ◽  
Author(s):  
Ling Zhao ◽  
Harufusa Toriumi ◽  
Yi Kuang ◽  
Huanchun Chen ◽  
Zhen F. Fu
Keyword(s):  
Virus Infection ◽  
Rabies Virus ◽  
Neurological Diseases ◽  
Inflammatory Cells ◽  
Dependent Manner ◽  
Recombinant Viruses ◽  
Inflammatory Protein ◽  
Growth Properties ◽  
High Level

ABSTRACT It was found previously that induction of innate immunity, particularly chemokines, is an important mechanism of rabies virus (RABV) attenuation. To evaluate the effect of overexpression of chemokines on RABV infection, chemokines macrophage inflammatory protein 1α (MIP-1α), RANTES, and IP-10 were individually cloned into the genome of attenuated RABV strain HEP-Flury. These recombinant RABVs were characterized in vitro for growth properties and expression of chemokines. It was found that all the recombinant viruses grew as well as the parent virus, and each of the viruses expressed the intended chemokine in a dose-dependent manner. When these viruses were evaluated for pathogenicity in the mouse model, it was found that overexpression of MIP-1α further decreased RABV pathogenicity by inducing a transient innate immune response. In contrast, overexpression of RANTES or IP-10 increased RABV pathogenicity by causing neurological diseases, which is due to persistent and high-level expression of chemokines, excessive infiltration and accumulation of inflammatory cells in the central nervous system, and severe enhancement of blood-brain barrier permeability. These studies indicate that overexpression of chemokines, although important in controlling virus infection, may not always be beneficial to the host.

scholarly journals Rabies Virus Infection Induces Type I Interferon Production in an IPS-1 Dependent Manner While Dendritic Cell Activation Relies on IFNAR Signaling

2010 ◽  
Vol 6 (7) ◽  
pp. e1001016 ◽  
Author(s):  
Elizabeth J. Faul ◽  
Celestine N. Wanjalla ◽  
Mehul S. Suthar ◽  
Michael Gale ◽  
Christoph Wirblich ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Virus Infection ◽  
Rabies Virus ◽  
Cell Activation ◽  
Type I Interferon ◽  
Type I ◽  
Dependent Manner ◽  
Interferon Production ◽  
Dendritic Cell Activation ◽  
Rabies Virus Infection

scholarly journals Long-Term Persistent Vesicular Stomatitis Virus and Rabies Virus Infection of Cells In Vitro

1976 ◽  
Vol 33 (2) ◽  
pp. 193-211 ◽  
Author(s):  
J. J. Holland ◽  
L. P. Villarreal ◽  
R. M. Welsh ◽  
M. B. A. Oldstone ◽  
D. Kohne ◽  
...  
Keyword(s):  
Virus Infection ◽  
Rabies Virus ◽  
Vesicular Stomatitis Virus ◽  
Rabies Virus Infection ◽  
Vesicular Stomatitis

scholarly journals Chloroquine, an Anti-Malaria Drug as Effective Prevention for Hantavirus Infections

2021 ◽  
Vol 11 ◽  
Author(s):  
Valentijn Vergote ◽  
Lies Laenen ◽  
Raf Mols ◽  
Patrick Augustijns ◽  
Marc Van Ranst ◽  
...  
Keyword(s):  
Virus Infection ◽  
Syrian Hamster ◽  
Osmotic Pump ◽  
Hantaan Virus ◽  
Dependent Manner ◽  
Prophylactic Effect ◽  
Hamster Model ◽  
Newborn Mice ◽  
Andes Virus

We investigated whether chloroquine can prevent hantavirus infection and disease in vitro and in vivo, using the Hantaan virus newborn C57BL/6 mice model and the Syrian hamster model for Andes virus. In vitro antiviral experiments were performed using Vero E6 cells, and Old World and New World hantavirus species. Hantavirus RNA was detected using quantitative RT-PCR. For all hantavirus species tested, results indicate that the IC50 of chloroquine (mean 10.2 ± 1.43 μM) is significantly lower than the CC50 (mean 260 ± 2.52 μM) yielding an overall selectivity index of 25.5. We also investigated the potential of chloroquine to prevent death in newborn mice after Hantaan virus infection and its antiviral effect in the hantavirus Syrian hamster model. For this purpose, C57Bl/6 mother mice were treated subcutaneously with daily doses of chloroquine. Subsequently, 1-day-old suckling mice were inoculated intracerebrally with 5 x 102 Hantaan virus particles. In litters of untreated mothers, none of the pups survived challenge. The highest survival rate (72.7% of pups) was found when mother mice were administered a concentration of 10 mg/kg chloroquine. Survival rates declined in a dose-dependent manner, with 47.6% survival when treated with 5 mg/kg chloroquine, and 4.2% when treated with 1 mg/kg chloroquine. Assessing the antiviral therapeutic and prophylactic effect of chloroquine in the Syrian hamster model was done using two different administration routes (intraperitoneally and subcutaneously using an osmotic pump system). Evaluating the prophylactic effect, a delay in onset of disease was noted and for the osmotic pump, 60% survival was observed. Our results show that chloroquine can be highly effective against Hantaan virus infection in newborn mice and against Andes virus in Syrian hamsters.

Identification of a transcriptional activator-binding element in the 27-kilodalton zein promoter, the -300 element

1994 ◽  
Vol 14 (7) ◽  
pp. 4350-4359
Author(s):  
T Ueda ◽  
Z Wang ◽  
N Pham ◽  
J Messing
Keyword(s):  
Transcriptional Activation ◽  
Transcriptional Activity ◽  
Expression System ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Suspension Cells ◽  
Factor Binding ◽  
High Level ◽  
Zein Genes

By utilizing a homologous transient-expression system, we have shown that a 58-bp sequence from the gamma-class 27-kDa zein promoter, spanning from -307 to -250 relative to the transcription start site, confers a high level of transcriptional activity on a truncated plant viral promoter. The transcriptional activity mediated by the 58-bp sequence is orientation independent, and it is further enhanced as a result of its multimerization. A similarly high level of transcriptional activity was also observed in protoplasts isolated from leaf tissue-derived maize suspension cells. In vitro binding and DNase I footprinting assays with nuclear protein prepared from cultured endosperm cells revealed the sequence-specific binding of a nuclear factor(s) to a 16-nucleotide sequence present in the 58-bp region. The nuclear factor binding sequence includes the -300 element, a cis-acting element highly conserved among different zein genes and many other cereal storage protein genes. A 23-bp oligonucleotide sequence containing the nuclear factor binding site is sufficient for binding the nuclear factor in vitro. It also confers a high level of transcriptional activity in vivo, but in an orientation-dependent manner. Four nucleotide substitutions in the -300 element drastically reduced binding and transcriptional activation by the nuclear factor. The same nuclear factor is abundant in the developing kernel endosperm and binds to the -300 element region of the 27-kDa or the alpha-class zein promoter. These results suggest that the highly conserved -300 element is involved in the common regulatory mechanisms mediating the coordinated expression of the zein genes.

scholarly journals Regulation of ATP-induced calcium release in COS-7 cells by calcineurin

2000 ◽  
Vol 348 (1) ◽  
pp. 173-181 ◽  
Author(s):  
Arun BANDYOPADHYAY ◽  
Dong-Wook SHIN ◽  
Do Han KIM
Keyword(s):  
Mammalian Cells ◽  
Calcium Release ◽  
Calcineurin Inhibitors ◽  
Dependent Manner ◽  
Transfected Cells ◽  
High Level ◽  
Dose Dependent ◽  
Constitutively Active

Experiments were conducted to examine the role of calcineurin in regulating Ca2+ fluxes in mammalian cells. In COS-7 cells, increasing concentrations (1-10 μM) of ATP triggered intracellular Ca2+ release in a dose-dependent manner. Treatment of the cells with calcineurin inhibitors such as cyclosporin A (CsA), deltamethrin and FK506 resulted in an enhancement of ATP-induced intracellular Ca2+ release. Measurement of calcineurin-specific phosphatase activity in vitro demonstrated a high level of endogenous calcineurin activities in COS-7 cells, which was effectively inhibited by the addition of deltamethrin or CsA. The expression of constitutively active calcineurin (CnA∆CaMAI) inhibited the ATP-induced increase in intracellular Ca2+ concentration ([Ca2+]i), in both the presence and the absence of extracellular Ca2+. These results suggest that the constitutively active calcineurin prevented Ca2+ release from the intracellular stores. In the calcineurin-transfected cells, treatment with CsA restored the calcineurin-mediated inhibition of intracellular Ca2+ release. Protein kinase C-mediated phosphorylation of Ins(1,4,5)P3 receptor [Ins(1,4,5)P3R] was partly inhibited by the extracts prepared from the vector-transfected cells and completely inhibited by those from cells co-transfected with CnA∆CaMAI and calcineurin B. On the addition of 10 μM CsA, the inhibited phosphorylation of Ins(1,4,5)P3R was restored in both the vector-transfected cells and the calcineurin-transfected cells. These results show direct evidence that Ca2+ release through Ins(1,4,5)P3R in COS-7 cells is regulated by calcineurin-mediated dephosphorylation.

scholarly journals Inhibition of Notch signaling pathway attenuates sympathetic hyperinnervation together with the augmentation of M2 macrophages in rats post-myocardial infarction

2016 ◽  
Vol 310 (1) ◽  
pp. C41-C53 ◽  
Author(s):  
Jie Yin ◽  
Hesheng Hu ◽  
Xiaolu Li ◽  
Mei Xue ◽  
Wenjuan Cheng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Butyl Ester ◽  
Surface Expression ◽  
Notch Signaling Pathway ◽  
M2 Macrophage ◽  
Coronary Artery Ligation ◽  
Dependent Manner ◽  
Artery Ligation ◽  
High Level

Inflammation-dominated sympathetic sprouting adjacent to the necrotic region following myocardial infarction (MI) has been implicated in the etiology of arrhythmias resulting in sudden cardiac death; however, the mechanisms responsible remain to be elucidated. Although being a key immune mediator, the role of Notch has yet to be explored. We investigated whether Notch regulates macrophage responses to inflammation and affects cardiac sympathetic reinnervation in rats undergoing MI. MI was induced by coronary artery ligation. A high level of Notch intracellular domain was observed in the macrophages that infiltrated the infarct area at 3 days post-MI. The administration of the Notch inhibitor N-N-(3,5-difluorophenacetyl-l-alanyl)-S-phenylglycine-t-butyl ester (DAPT) (intravenously 30 min before MI and then daily until death) decreased the number of macrophages and significantly increased the M2 macrophage activation profile in the early stages and attenuated the expression of nerve growth factor (NGF). Eventually, NGF-induced sympathetic hyperinnervation was blunted, as assessed by the immunofluorescence of tyrosine hydroxylase. At 7 days post-MI, the arrhythmia score of programmed electric stimulation in the vehicle-treated infarcted rats was higher than that in rats treated with DAPT. Further deterioration in cardiac function and decreases in the plasma levels of TNF-α and IL-1β were also detected. In vitro studies revealed that LPS/IFN-γ upregulated the surface expression of NGF in M1 macrophages in a Notch-dependent manner. We concluded that Notch inhibition during the acute inflammatory response phase is associated with the downregulation of NGF, probably through a macrophage-dependent pathway, thus preventing the process of sympathetic hyperinnervation.

scholarly journals Recombinant rabies virus expressing chimeric Omp31/sodC or AHCY gene from Brucella melitensis elicits high level of antibodies and secretary cytokines in mice

2019 ◽  
Author(s):  
Zhenguang Li ◽  
Hongwei Zhu ◽  
Yanling Yang ◽  
Fengxue Wang ◽  
Menghang Wang ◽  
...  
Keyword(s):  
Rabies Virus ◽  
Humoral Immunity ◽  
Recombinant Virus ◽  
Reverse Genetics ◽  
Brucella Melitensis ◽  
Mrna Level ◽  
Neutralizing Antibody ◽  
Growth Properties ◽  
Cellular And Humoral Immunity ◽  
High Level

Abstract Background: The rabies virus (RV) vector LBNSE expressing foreign antigens has shown considerable promise as vaccines against viral and bacteria diseases, which is effective and safe. We produced a new RV-based vaccine vehicle expressing Brucella melitensis Omp31/sodC or AHCY gene by reverse genetics technology. The aim of this study was to investigate the cellular and humoral immunity of recombinant viruses. Results: The recombinant virus rLBNSE-SOD and rLBNSE-AHC retained growth properties similar to those of vector rLBNSE both in BSR and mNA cell culture. The Omp31/SODC and AHCY gene was expressed and detected by immunostaining. To compare the immunogenicity of LBNSE-SOD and LBNSE-AHC, mice were immunized with each of recombinant virus by intramuscular (i.m.). Then mice were bled at days 7, 14 after the immunization for the measurement of cytokines and virus neutralizing antibody (VNAs). The parent virus (LBNSE) without expression of any foreign molecules was included for comparison. It was found that mice inoculated with LBNSE-SOD and LBNSE-AHC showed no any signs of disease and exhibited seroconversion against RV. Our findings showed that mice were immunized with each of these recombinant RVs by intramuscular (i.m.) developed efficacy cellular and humoral immunity. The mRNA level of cytokines (IFN-γ and IL-2; IL-4 and IL-10) and VNA level against rabies virus in the blood of mice were increasing after immunization with recombinant RVs. There were no obvious histopathological changes in the brain samples of all mice. Conclusions: The studies suggested that recombinant RVs expressing Omp31/SodC or AHCY gene would elicit high level of antibodies and secretary cytokines and provided a promising vaccine candidate in mice.

scholarly journals RNA-Containing Immune Complexes Formed by Anti-Melanoma Differentiation Associated Gene 5 Autoantibody Are Potent Inducers of IFN-α

2021 ◽  
Vol 12 ◽  
Author(s):  
Kaiwen Wang ◽  
Jiangfeng Zhao ◽  
Wanlong Wu ◽  
Wenwen Xu ◽  
Shuhui Sun ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Enzyme Linked Immunosorbent Assay ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Cytoplasmic Rna ◽  
Healthy Donors ◽  
Rna Immunoprecipitation ◽  
High Level

ObjectiveAnti-melanoma differentiation-associated gene 5 (MDA5) autoantibody is a distinctive serology hallmark of dermatomyositis (DM). As an autoantigen, MDA5 is a cytoplasmic RNA recognition receptor. The aim of this study was to address the question of whether the RNA-containing immune complex (IC) formed by MDA5 and anti-MDA5 could activate type I interferon (IFN) response.MethodPatients with anti-MDA5+ DM (n = 217), anti-MDA5− DM (n = 68), anti-synthase syndrome (ASyS, n = 57), systemic lupus erythematosus (SLE, n = 245), rheumatoid arthritis (RA, n = 89), and systemic sclerosis (SSc, n = 30) and healthy donors (HD, n = 94) were enrolled in our studies. Anti-MDA5 antibody was detected by line blotting, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, and Western blotting. Cytokine profiling was determined by multiplex flow cytometry, and IFN-α was further measured by ELISA. Type I IFN-inducible genes were detected by quantitative PCR (qPCR). RNA–IC binding was analyzed by RNA immunoprecipitation. Plasmacytoid dendritic cells (pDCs) derived from healthy donors were cultivated and stimulated with MDA5 ICs with or without RNase and Toll-like receptor 7 (TLR-7) agonist. The interaction between MDA5 ICs and TLR7 was evaluated by immunoprecipitation and confocal microscopy.ResultsAccording to our in-house ELISA, the presence of anti-MDA5 antibody in 76.1% of DM patients, along with 14.3% of SLE patients who had a lower titer yet positive anti-MDA5 antibody, was related to the high level of peripheral IFN-α. ICs formed by MDA5 and anti-MDA5 were potent inducers of IFN-α via TLR-7 in an RNA-dependent manner in vitro.ConclusionOur data provided evidence of the mechanistic relevance between the anti-MDA5 antibody and type I IFN pathway.

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