scholarly journals Increased activity of indoleamine 2,3-dioxygenase in serum from acutely infected dengue patients linked to gamma interferon antiviral function

2009 ◽  
Vol 90 (4) ◽  
pp. 810-817 ◽  
Author(s):  
Aniuska Becerra ◽  
Rajas V. Warke ◽  
Kris Xhaja ◽  
Barbara Evans ◽  
James Evans ◽  
...  
Keyword(s):  
Antiviral Effect ◽  
Denv Infection ◽  
Gamma Interferon ◽  
Indoleamine 2,3 Dioxygenase ◽  
Inhibition Of Growth ◽  
Healthy Donors ◽  
Antiviral Function ◽  
Micro Organisms

The depletion of l-tryptophan (L-Trp) has been associated with the inhibition of growth of micro-organisms and also has profound effects on T cell proliferation and immune tolerance. The enzyme indoleamine 2,3-dioxygenase (IDO) catalyses the rate-limiting step in the catabolic pathway of L-Trp. Gene expression analysis has shown upregulation of genes involved in L-Trp catabolism in in vitro models of dengue virus (DENV) infection. To understand the role of IDO during DENV infection, we measured IDO activity in sera from control and DENV-infected patients. We found increased IDO activity, lower levels of L-Trp and higher levels of l-kynurenine in sera from DENV-infected patients during the febrile days of the disease compared with patients with other febrile illnesses and healthy donors. Furthermore, we confirmed upregulation of IDO mRNA expression in response to DENV infection in vitro, using a dendritic cell (DC) model of DENV infection. We found that the antiviral effect of gamma interferon (IFN-γ) in DENV-infected DCs in vitro was partially dependent on IDO activity. Our results demonstrate that IDO plays an important role in the antiviral effect of IFN-γ against DENV infection in vitro and suggest that it has a role in the immune response to DENV infections in vivo.

scholarly journals Human Polyomavirus Type 1 (BK Virus) Agnoprotein Is Abundantly Expressed but Immunologically Ignored

2007 ◽  
Vol 14 (8) ◽  
pp. 959-968 ◽  
Author(s):  
David Leuenberger ◽  
Per Arne Andresen ◽  
Rainer Gosert ◽  
Simone Binggeli ◽  
Erik H. Ström ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Bk Virus ◽  
Gamma Interferon ◽  
Human Polyomavirus ◽  
Large Tumor ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Cellular Immune

ABSTRACT Impaired BK virus (BKV)-specific immunity is a key risk factor of polyomavirus-associated nephropathy. We hypothesized that BKV agnoprotein might constitute an important immune target, as it is highly expressed after infection in vitro. We demonstrate abundant expression of BKV agnoprotein in vivo by immunostaining of kidney transplant (KT) biopsy specimens. Antibody responses to the recombinant affinity-purified BKV agnoprotein, large tumor (LT), and VP1 antigens in 146 sera from 38 KT patients and in 19 sera from 16 healthy donors (HD) were compared by enzyme immunoassay. In HD, low titers of anti-agnoprotein immunoglobulin G (IgG) were found in 15% of sera, compared to 41% for anti-LT antigen and 63% for anti-VP1. No anti-BKV IgM was detectable. In KT patients, anti-agnoprotein IgG and IgM were found in 8% and 3.6% of sera, compared to 63% and 18% for anti-LT IgG and IgM and 80% and 41% for anti-VP1 IgG and IgM, respectively. Anti-LT antigen and anti-VP1, but not anti-agnoprotein, activities increased during and after BKV viremia in KT patients. To investigate specific cellular immune responses, we compared levels of gamma interferon production in peripheral blood mononuclear cells (PBMC) of 10 HD and 30 KT patients by enzyme-linked immunospot assay. In HD, the median numbers of gamma interferon spot-forming units per million PBMC for the agnoprotein, LT antigen, and VP1 peptides were 1, 23, and 25, respectively, whereas the responses in KT patients were 2, 24, and 99, respectively. We conclude that BKV agnoprotein, though abundantly expressed in vivo, is poorly recognized immunologically.

scholarly journals Repurposing the Antiemetic Metoclopramide as an Antiviral Against Dengue Virus Infection in Neuronal Cells

2021 ◽  
Vol 10 ◽  
Author(s):  
Ting-Jing Shen ◽  
Vu Thi Hanh ◽  
Thai Quoc Nguyen ◽  
Ming-Kai Jhan ◽  
Min-Ru Ho ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Cell Line ◽  
Plaque Assay ◽  
Neuronal Cell ◽  
Antiviral Effect ◽  
Denv Infection ◽  
New Drugs ◽  
Dopamine 2 Receptor

Dengue virus (DENV) is transmitted by Aedes mosquitoes to humans and is a threat worldwide. No effective new drugs have been used for anti-dengue treatment, and repurposing drugs is an alternative approach to treat this condition. Dopamine 2 receptor (D2R) is a host receptor positively associated with DENV infection. Metoclopramide (MCP), a D2R antagonist clinically used to control vomiting and nausea in patients with DENV infection, was putatively examined for inhibition of DENV infection by targeting D2R. In the mouse neural cell line Neuro-2a with D2R expression, a plaque assay demonstrated the antiviral efficacy of MCP treatment. However, in the cell line BHK-21, which did not express D2R, MCP treatment caused no further inhibition of DENV infection. Either MCP treatment or exogenous administration of a neutralizing D2R antibody blocked DENV binding. Treatment with MCP also reduced DENV dsRNA replication and DENV-induced neuronal cell cytotoxicity in vitro. An in vivo study demonstrated the antiviral effect of MCP against DENV-induced CNS neuropathy and mortality. These results showed that repurposing the D2R-targeting antiemetic MCP is a potential therapeutic strategy against DENV infection.

scholarly journals T cell mediated hypersensitivity to previously tolerated iodinated contrast media precipitated by introduction of atezolizumab

2021 ◽  
Vol 9 (5) ◽  
pp. e002521
Author(s):  
Sean Hammond ◽  
Anna Olsson-Brown ◽  
Joshua Gardner ◽  
Paul Thomson ◽  
Serat-E Ali ◽  
...  
Keyword(s):  
Contrast Media ◽  
Adverse Reactions ◽  
Stevens Johnson Syndrome ◽  
Iodinated Contrast ◽  
Immune Mediated ◽  
Johnson Syndrome ◽  
Healthy Donors ◽  
Concomitant Medications

Many adverse reactions associated with immune checkpoint inhibitor (ICI) treatments are immunologically driven and may necessitate discontinuation of the ICI. Herein, we present a patient who had been administered the radio contrast media amidotrizoate multiple times without issue but who then developed a Stevens-Johnson syndrome reaction after coadministration of atezolizumab. Causality was confirmed by a positive re-challenge with amidotrizoate and laboratory investigations that implicated T cells. Importantly, the introduction of atezolizumab appears to have altered the immunologic response to amidotrizoate in terms of the tolerance–elicitation continuum. Proof of concept studies demonstrated enhancement of recall responses to a surrogate antigen panel following in-vitro (healthy donors) and in-vivo (ICI patients) administrations of ICIs. Our findings highlight the importance of considering all concomitant medications in patients on ICIs who develop immune-mediated adverse reactions. In the event of some immune-related adverse reactions, it may be critical to identify the culprit antigen-forming entity that the ICIs have altered the perception of rather than simply attribute causality to the ICI itself in order to optimize both patient safety and treatment of malignancies.

scholarly journals Interferon beta-1a induces expression of brain-derived neurotrophic factor in human T lymphocytes in vitro and not in vivo

2020 ◽  
Vol 15 (1) ◽  
pp. FNL38 ◽  
Author(s):  
Zarlascht Karmand ◽  
Hans-Peter Hartung ◽  
Oliver Neuhaus
Keyword(s):  
T Cell ◽  
Neurotrophic Factor ◽  
Serum Levels ◽  
Brain Derived Neurotrophic Factor ◽  
Peripheral Blood Lymphocytes ◽  
T Cell Proliferation ◽  
Bdnf Expression ◽  
Healthy Donors

Aim: To detect IFN β-1a-induced expression of brain-derived neurotrophic factor (BDNF) to undermine the hypothesis of IFN β-1a-associated neuroprotection in multiple sclerosis (MS). Methods: The influence of IFN β-1a on in vitro activated peripheral blood lymphocytes from healthy donors was tested. Proliferation analyses were made to detect T-cell growth. BDNF expression was measured by standard ELISA. To assess the influence of IFN β-1a on BDNF expression in vivo, BDNF serum levels of MS patients treated with IFN β-1a were compared with those of untreated patients. Results: IFN β-1a inhibited T-cell proliferation dose dependently. It induced BDNF expression at middle concentrations. MS patients treated with IFN β-1a exhibited significantly lower BDNF serum levels than untreated patients. Conclusion: IFN β-1a may promote neuroprotection by inducing BDNF expression, but its importance in vivo remains open.

scholarly journals The Antiviral Effect of Novel Steroidal Derivatives on Flaviviruses

2021 ◽  
Vol 12 ◽  
Author(s):  
Luping Zhang ◽  
Dengyuan Zhou ◽  
Qiuyan Li ◽  
Shuo Zhu ◽  
Muhammad Imran ◽  
...  
Keyword(s):  
Antiviral Effect ◽  
Therapeutic Drug ◽  
Dependent Manner ◽  
Design And Synthesis ◽  
Invasion Stage ◽  
Synthetic Derivatives ◽  
Dose Dependent ◽  
The Brain

Flaviviruses are the major emerging arthropod-borne pathogens globally. However, there is still no practical anti-flavivirus approach. Therefore, existing and emerging flaviviruses desperately need active broad-spectrum drugs. In the present study, the antiviral effect of steroidal dehydroepiandrosterone (DHEA) and 23 synthetic derivatives against flaviviruses such as Japanese encephalitis virus (JEV), Zika virus (ZIKV), and Dengue virus (DENV) were appraised by examining the characteristics of virus infection both in vitro and in vivo. Our results revealed that AV1003, AV1004 and AV1017 were the most potent inhibitors of flavivirus propagation in cells. They mainly suppress the viral infection in the post-invasion stage in a dose-dependent manner. Furthermore, orally administered compound AV1004 protected mice from lethal JEV infection by increasing the survival rate and reducing the viral load in the brain of infected mice. These results indicate that the compound AV1004 might be a potential therapeutic drug against JEV infection. These DHEA derivatives may provide lead scaffolds for further design and synthesis of potential anti-flavivirus potential drugs.

scholarly journals Pharmacological modulation of cell functional activity with valproic acid and erythropoietin

2019 ◽  
Vol 5 (2) ◽  
pp. 89-99
Author(s):  
Polina A. Golubinskaya ◽  
Marina V. Sarycheva ◽  
Svetlana Y. Burda ◽  
Maksim V. Puzanov ◽  
Natalya A. Nadezhdina ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Antiepileptic Drug ◽  
Axial Skeleton ◽  
Pharmacological Modulation ◽  
Inhibition Of Growth ◽  
Acid Effect ◽  
Branched Chain ◽  
Growth Of Tumor

Introduction: Valproic acid (VA) is carboxylic acid with a branched chain, which is used as an antiepileptic drug. Valproic acid influence on cells in vivo: VA, which is an antiepileptic drug, is also a teratogen, which causes defects of a neural tube and an axial skeleton, although the mechanisms are not yet fully clear. Valproic acid influence on mesenchymal stem cells (MSC) in vitro: It is shown that valproic acid reduces the intracellular level of oxygen active forms. Valproic acid effect on tumor cells: VA inhibits tumor growth through several mechanisms, including the cell cycle stop, differentiation induction and inhibition of growth of tumor vessels. Valproic acid influence on enzymes: It affects mainly GSK-3. Valproic acid influence on animals’ cells: It is shown that VA can significantly improve an ability to develop in vitro and improve nuclear reprogramming of embryos. Erythropoietin (EPO): Is an hypoxia-induced hormone and a cytokine, which is necessary for normal erythropoiesis. EPO is widely used in in vitro experiments. Conclusion: Thus, the influence of VA and EPO on cells can be used in cell technologies.

scholarly journals Development of a Human Gamma Interferon Enzyme Immunoassay and Comparison with Tuberculin Skin Testing for Detection ofMycobacterium tuberculosis Infection

1998 ◽  
Vol 5 (4) ◽  
pp. 531-536 ◽  
Author(s):  
Nuket Desem ◽  
Stephen L. Jones
Keyword(s):  
Enzyme Immunoassay ◽  
Skin Test ◽  
Skin Testing ◽  
Gamma Interferon ◽  
Tuberculin Skin Testing ◽  
In Vitro Test ◽  
Detection Range ◽  
Ifn Γ

ABSTRACT A sensitive two-step simultaneous enzyme immunoassay (EIA) for human gamma interferon (IFN-γ) has been developed and used as an in vitro test for human tuberculosis (TB) in comparison with tuberculin skin testing. The EIA was shown to be highly sensitive, detecting less than 0.5 IU of recombinant human IFN-γ per ml within a linear detection range of 0.5 to 150 IU/ml. The assay was highly reproducible and specific for native IFN-γ. In addition, the assay detected chimpanzee, orangutan, gibbon, and squirrel monkey IFN-γs. Cross-reactions with other human cytokines or with IFN-γs derived from mice, cattle, or Old World monkeys were not evident. The assay was used to detect TB infection by incubating whole blood overnight with human, avian, and bovine tuberculin purified protein derivatives (PPDs), as well as positive (mitogen)- and negative-control preparations. The levels of IFN-γ in plasma supernatants were then determined. Blood from 10 tuberculin skin test-positive individuals responded predominantly to the human tuberculin PPD antigen and to a lesser extent to bovine and avian PPD antigens. By contrast, blood from 10 skin test-negative individuals showed minimal responses or no response to any of the tuberculin PPDs. Detectable levels of IFN-γ were present in all blood samples stimulated with mitogen. In vivo tuberculin reactivity was correlated with IFN-γ responsiveness in vitro. These results support the further study of the blood culture–IFN-γ EIA system as an alternative to skin testing for the detection of human TB infection.

scholarly journals Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing

2021 ◽  
Vol 12 ◽  
Author(s):  
Charlotte Kern ◽  
Verena Schöning ◽  
Carlos Chaccour ◽  
Felix Hammann
Keyword(s):  
Drug Repurposing ◽  
Antiviral Effect ◽  
Drug Candidate ◽  
Appreciable Effect ◽  
Viral Kinetics ◽  
Future Drug ◽  
Dosing Regimens ◽  
Clinical Trial Results

Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro, an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3–0.6 log units and exposure by 8.8–22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts.

scholarly journals Viperin is anti-viral in vitro but is dispensable for restricting dengue virus replication or induction of innate and inflammatory responses in vivo

2021 ◽  
Vol 102 (10) ◽  
Author(s):  
Wisam-Hamzah Al Shujairi ◽  
Luke P. Kris ◽  
Kylie van der Hoek ◽  
Evangeline Cowell ◽  
Gustavo Bracho-Granado ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Denv Infection ◽  
Brain Morphology ◽  
Moderate Increase ◽  
Tnf Α ◽  
Significant Difference

Viperin has antiviral function against many viruses, including dengue virus (DENV), when studied in cells in culture. Here, the antiviral actions of viperin were defined both in vitro and in a mouse in vivo model of DENV infection. Murine embryonic fibroblasts (MEFs) derived from mice lacking viperin (vip−/−) showed enhanced DENV infection, accompanied by increased IFN-β and induction of ISGs; IFIT1 and CXCL-10 but not IRF7, when compared to wild-type (WT) MEFs. In contrast, subcutaneous challenge of immunocompetent WT and vip−/− mice with DENV did not result in enhanced infection. Intracranial infection with DENV resulted in body weight loss and neurological disease with a moderate increase in mortality in vip−/− compared with WT mice, although this was not accompanied by altered brain morphology, immune cell infiltration or DENV RNA level in the brain. Similarly, DENV induction of IFN-β, IFIT1, CXCL-10, IRF7 and TNF-α was not significantly different in WT and vip−/− mouse brain, although there was a modest but significant increase in DENV induction of IL-6 and IfI27la in the absence of viperin. NanoString nCounter analysis confirmed no significant difference in induction of a panel of inflammatory genes in WT compared to vip−/− DENV-infected mouse brains. Further, polyI:C stimulation of bone marrow-derived macrophages (BMDMs) induced TNF-α, IFN-β, IL-6 and Nos-2, but responses were not different in BMDMs generated from WT or vip−/− mice. Thus, while there is significant evidence of anti-DENV actions of viperin in some cell types in vitro, for DENV infection in vivo a lack of viperin does not affect systemic or brain susceptibility to DENV or induction of innate and inflammatory responses.

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