1-Formyl-β-carboline Derivatives Block Newcastle Disease Virus Proliferation through Suppressing Viral Adsorption and Entry Processes

Newcastle disease virus (NDV) is one of the highly contagious pathogens causing devastating economic effects on the global poultry industry. In the present study, three 1-formyl-β-carboline derivatives (compounds 6, 7, and 9) were found to be potent inhibitors of different genotypes of NDV with IC50 values within 10 μM, which are similar to ribavirin. The virus titers were decreased by the presence of 1-formyl-β-carboline derivatives in a dose-dependent manner, and the inhibition rate was found to exceed 90% at the concentration of 20 μM. These compounds mainly suppressed the adsorption and entry processes of NDV lifecycle. Through DARTS, CETSA, and RBC binding assay, these compounds were identified as novel HN inhibitors, which could directly interact with the NDV HN protein to affect the adsorption of NDV. Furthermore, they could inhibit the entry of NDV through suppressing the PI3K/Akt pathway rather than the ERK pathway. The PI3K/Akt pathway was proved to be involved in NDV entry. Our findings reveal a unique mechanism through which 1-formyl-β-carboline derivatives restrain NDV infection. Moreover, these compounds represent suitable scaffolds for designing novel HN inhibitors.

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Mechanisms and consequences of Newcastle disease virus W protein subcellular localization in the nucleus or mitochondria

Journal of Virology ◽

10.1128/jvi.02087-20 ◽

2021 ◽

Author(s):

Yanling Yang ◽

Jia Xue ◽

Qingyuan Teng ◽

Xiao Li ◽

Yawen Bu ◽

...

Keyword(s):

Newcastle Disease Virus ◽

Disease Virus ◽

Nuclear Localization ◽

Newcastle Disease ◽

Nuclear Export ◽

Protein Localization ◽

Dependent Manner ◽

V Protein ◽

Terminal Domain ◽

P Gene

We previously demonstrated that W proteins from different Newcastle disease virus (NDV) strains localize in either the cytoplasm (e.g., NDV strain SG10) or the nucleus (e.g., NDV strain La Sota). To clarify the mechanism behind these cell localization differences, we overexpressed W protein derived from four different NDV strains or W protein associated with different cellular regions in Vero cells. This revealed that the key region for determining W protein localization is 180–227aa. Further experiments found that there is a nuclear export signal (NES) motif in W protein 211–224aa. W protein could be transported into the nucleus via interaction with KPNA1, KPNA2, and KPNA6 in a nuclear localization signal-dependent manner, and W protein containing an NES was transported back to the cytoplasm in a CRM1-independent manner. Interestingly, we observed that the cytoplasm-localized W protein colocalizes with mitochondria. We rescued the NES-deletion W protein NDV strain rSG10-ΔWC/WΔNES using an NDV reverse genetics system and found that the replication ability, virulence, and pathogenicity of an NDV strain were all higher when the W protein cellular localization was in the nucleus rather than the mitochondria. Further experiments revealed that W protein nuclear localization reduced the expression of IFN-β otherwise stimulated by NDV. Our research reveals the mechanism by which NDV W protein becomes localized to different parts of the cell and demonstrates the outcomes of nuclear or cytoplasmic localization both in vitro and in vivo, laying a foundation for subsequent functional studies of the W protein in NDV and other paramyxoviruses. IMPORTANCE In Newcastle disease virus (NDV), the W protein, like the V protein, is a nonstructural protein encoded by the P gene via RNA editing. Compared with V protein, W protein has a common N-terminal domain but a unique C-terminal domain. V protein is known as a key virulence factor and an important interferon antagonist across the family Paramyxoviridae. In contrast, very little is known about the function of NDV W protein, and this limited information is based on studies of the Nipah virus W protein. Here, we investigated the localization mechanism of NDV W protein and its subcellular distribution in mitochondria. We found that W protein localization differences impact IFN-β production, consequently affecting NDV virulence, replication, and pathogenicity. This work provides new insights on the differential localization mechanism of NDV W proteins, along with fundamental knowledge for understanding the functions of W proteins in NDV and other paramyxoviruses.

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Virus-Like Particle Vaccine Confers Protection against a Lethal Newcastle Disease Virus Challenge in Chickens and Allows a Strategy of Differentiating Infected from Vaccinated Animals

Clinical and Vaccine Immunology ◽

10.1128/cvi.00636-13 ◽

2014 ◽

Vol 21 (3) ◽

pp. 360-365 ◽

Cited By ~ 15

Author(s):

Jae-Keun Park ◽

Dong-Hun Lee ◽

Seong-Su Yuk ◽

Erdene-Ochir Tseren-Ochir ◽

Jung-Hoon Kwon ◽

...

Keyword(s):

Newcastle Disease Virus ◽

Disease Virus ◽

Newcastle Disease ◽

Protective Efficacy ◽

Expression System ◽

Enzyme Linked Immunosorbent Assay ◽

Dependent Manner ◽

Lethal Challenge ◽

Challenge Virus ◽

Virus Challenge

ABSTRACTIn this study, we developed Newcastle disease virus (NDV) virus-like particles (VLPs) expressing NDV fusion (F) protein along with influenza virus matrix 1 (M1) protein using the insect cell expression system. Specific-pathogen-free chickens were immunized with oil emulsion NDV VLP vaccines containing increasing dosages of VLPs (0.4, 2, 10, or 50 μg of VLPs/0.5-ml dose). Three weeks after immunization, the immunogenicity of the NDV VLP vaccines was determined using a commercial enzyme-linked immunosorbent assay (ELISA) kit, and a lethal challenge using a highly virulent NDV strain was performed to evaluate the protective efficacy of the NDV VLP vaccines. NDV VLP vaccines elicited anti-NDV antibodies and provided protection against a lethal challenge in a dose-dependent manner. Although the VLP vaccines containing 0.4 and 2 μg of VLPs failed to achieve high levels of protection, a single immunization with NDV VLP vaccine containing 10 or 50 μg could fully protect chickens from a lethal challenge and greatly reduced challenge virus shedding. Furthermore, we could easily differentiate infected from vaccinated animals (DIVA) using the hemagglutination inhibition (HI) test. These results strongly suggest that utilization of NDV VLP vaccine in poultry species may be a promising strategy for the better control of NDV.

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Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma

British Journal of Cancer ◽

10.1038/s41416-019-0639-7 ◽

2019 ◽

Vol 122 (1) ◽

pp. 111-120 ◽

Cited By ~ 5

Author(s):

Gang Meng ◽

Binghua Li ◽

Anxian Chen ◽

Meihong Zheng ◽

Tiancheng Xu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Newcastle Disease Virus ◽

Disease Virus ◽

Negative Feedback ◽

Newcastle Disease ◽

Aerobic Glycolysis ◽

Suppressor Cell ◽

Oncolytic Viruses ◽

Pyruvate Dehydrogenase Kinase ◽

Dependent Manner

Abstract Background Oncolytic viro-immunotherapy holds promise for cancer treatment. While immune activation can be robustly triggered by oncolytic viruses, negative feedback is often upregulated in the tumour microenvironment (TME). Lactate accumulation, signal transducer and activator of transcription 3 (STAT3) activation, indoleamine 2,3-dioxygenase 1 (IDO1) expression, and myeloid-derived suppressor cell (MDSC) infiltration coordinate to shape the immunosuppressive TME. Methods Representative hepatocellular carcinoma (HCC) cell lines and HCC-bearing mice were treated with oncolytic Newcastle disease virus (NDV), alone or in combination with dichloroacetate (DCA, a pyruvate dehydrogenase kinase (PDK) inhibitor). Results We found that infection with oncolytic NDV led to significant induction of the aforementioned suppressive factors. Interestingly, DCA significantly reduced lactate release, STAT3 activation, IDO1 upregulation, and MDSC infiltration in NDV-treated HCC. Consequently, DCA significantly enhanced the antitumour immune responses, leading to improved antitumour efficacy and prolonged survival in mouse models of ascitic and subcutaneous HCC. Furthermore, DCA increased NDV replication in a PDK-1-dependent manner in HCC. Conclusions Targeting aerobic glycolysis by DCA improves NDV-mediated viro-immunotherapy in HCC by mitigating immune negative feedback and promoting viral replication. These findings provide a rationale for targeting reprogrammed metabolism together with oncolytic virus-mediated viro-immunotherapy for HCC treatment.

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Chicken bromodomain-containing protein 2 interacts with the Newcastle disease virus matrix protein and promotes viral replication

Veterinary Research ◽

10.1186/s13567-020-00846-1 ◽

2020 ◽

Vol 51 (1) ◽

Author(s):

Zhiqiang Duan ◽

Yifan Han ◽

Lei Zhou ◽

Chao Yuan ◽

Yanbi Wang ◽

...

Keyword(s):

Newcastle Disease Virus ◽

Disease Virus ◽

Newcastle Disease ◽

Transcriptional Control ◽

Rna Synthesis ◽

Matrix Protein ◽

Viral Rna ◽

M Protein ◽

Dependent Manner ◽

Binding Studies

Abstract Bromodomain-containing protein 2 (BRD2) is a nucleus-localized serine-threonine kinase that plays pivotal roles in the transcriptional control of diverse genes. In our previous study, the chicken BRD2 (chBRD2) protein was found to interact with the Newcastle disease virus (NDV) matrix (M) protein using a yeast two-hybrid screening system, but the role of the chBRD2 protein in the replication of NDV remains unclear. In this study, we first confirmed the interaction between the M protein and chBRD2 protein using fluorescence co-localization, co-immunoprecipitation and pull-down assays. Intracellular binding studies indicated that the C-terminus (aa 264–313) of the M protein and the extra-terminal (ET) domain (aa 619–683) of the chBRD2 protein were responsible for interactions with each other. Interestingly, although two amino acids (T621 and S649) found in the chBRD2/ET domain were different from those in the human BRD2/ET domain and in that of other mammals, they did not disrupt the BRD2-M interaction or the chBRD2-M interaction. In addition, we found that the transcription of the chBRD2 gene was obviously decreased in both NDV-infected cells and pEGFP-M-transfected cells in a dose-dependent manner. Moreover, small interfering RNA-mediated knockdown of chBRD2 or overexpression of chBRD2 remarkably enhanced or reduced NDV replication by upregulating or downregulating viral RNA synthesis and transcription, respectively. Overall, we demonstrate for the first time that the interaction of the M protein with the chBRD2 protein in the nucleus promotes NDV replication by downregulating chBRD2 expression and facilitating viral RNA synthesis and transcription. These results will provide further insight into the biological functions of the M protein in the replication of NDV.

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Synergy or interference of a H9N2 avian influenza virus with a velogenic Newcastle disease virus in chickens is dose dependent

Avian Pathology ◽

10.1080/03079457.2017.1319904 ◽

2017 ◽

Vol 46 (5) ◽

pp. 488-496 ◽

Cited By ~ 8

Author(s):

Francesco Bonfante ◽

Giovanni Cattoli ◽

Sofia Leardini ◽

Angela Salomoni ◽

Eva Mazzetto ◽

...

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Newcastle Disease Virus ◽

Avian Influenza Virus ◽

Disease Virus ◽

Newcastle Disease ◽

H9n2 Avian Influenza Virus ◽

Velogenic Newcastle Disease Virus ◽

Dose Dependent

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Transient activation of the PI3K/Akt pathway promotes Newcastle disease virus replication and enhances anti-apoptotic signaling responses

Oncotarget ◽

10.18632/oncotarget.15796 ◽

2017 ◽

Vol 8 (14) ◽

pp. 23551-23563 ◽

Cited By ~ 14

Author(s):

Yinfeng Kang ◽

Runyu Yuan ◽

Xiaqiong Zhao ◽

Bin Xiang ◽

Shimin Gao ◽

...

Keyword(s):

Newcastle Disease Virus ◽

Disease Virus ◽

Virus Replication ◽

Newcastle Disease ◽

Akt Pathway ◽

Apoptotic Signaling ◽

Transient Activation

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Dose-dependent Effect of T-2 Toxin on the Immunity against Newcastle Disease Virus in Chickens

Acta Veterinaria Brno ◽

10.2754/avb200675030387 ◽

2006 ◽

Vol 75 (3) ◽

pp. 387-391 ◽

Cited By ~ 3

Author(s):

M. Weber ◽

J. Fodor ◽

K. Balogh ◽

M. Erdélyi ◽

M. Mézes

Keyword(s):

Newcastle Disease Virus ◽

Disease Virus ◽

Newcastle Disease ◽

Broiler Chickens ◽

Haemagglutination Inhibition ◽

Control Group ◽

Published Data ◽

Intact Control ◽

Group 2 ◽

Dose Dependent

The effect of 2.35 (a) and 4.18 (b) mg kg-1 feed T-2 toxin dose for 14 days on the haemagglutination inhibition titres against Newcastle disease virus was investigated in broiler chickens. The animals were divided into four groups and two separate experiments were carried out (a, b): (1) intact control group; (2) birds were fed with T-2 toxin contaminated feed and not vaccinated; (3) repeatedly vaccinated (on day 23 of age) control group which received uncontaminated feed; (4) birds were both repeatedly vaccinated and fed the T-2 toxin contaminated diet. Blood samples, from which sera titres were measured, were taken on days 7 and 14 of the experiments. It was found that heamagglutination titres were different in the two experiments even in the control (1) group because of the different efficiency of the first immunization at the hatchery. Titres on day 7 showed increases in all groups except for the group fed lower T-2 contaminated diet (a, group 2) but during the second week they increased only in the groups fed the diet with a lower dose of T-2 toxin. On the contrary, a higher dose of T-2 toxin contamination of the diet resulted in a dramatic decrease during the second week (b, groups 2 and 4). The results suggested that contrary to most of the previously published data, feeding of T-2 toxin contaminated feed with an amount of 2.35 mg.kg-1 did not decrease, but increase the antibody formation against attenuated Newcastle disease virus even without a second vaccination on day 1 of the experiment, whereas a higher amount of T-2 toxin (4.18 mg kg-1) decreased to day 14 after the repeated vaccination.

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