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Journal of Virology Mar 2023Viruses require host cell metabolic reprogramming to satisfy their replication demands; however, the mechanism by which the Newcastle disease virus (NDV) remodels...
Viruses require host cell metabolic reprogramming to satisfy their replication demands; however, the mechanism by which the Newcastle disease virus (NDV) remodels nucleotide metabolism to support self-replication remains unknown. In this study, we demonstrate that NDV relies on the oxidative pentose phosphate pathway (oxPPP) and the folate-mediated one-carbon metabolic pathway to support replication. In concert with [1,2-C] glucose metabolic flow, NDV used oxPPP to promote pentose phosphate synthesis and to increase antioxidant NADPH production. Metabolic flux experiments using [2,3,3-H] serine revealed that NDV increased one-carbon (1C) unit synthesis flux through the mitochondrial 1C pathway. Interestingly, methylenetetrahydrofolate dehydrogenase (MTHFD2) was upregulated as a compensatory mechanism for insufficient serine availability. Unexpectedly, direct knockdown of enzymes in the one-carbon metabolic pathway, except for cytosolic MTHFD1, significantly inhibited NDV replication. Specific complementation rescue experiments on small interfering RNA (siRNA)-mediated knockdown further revealed that only a knockdown of MTHFD2 strongly restrained NDV replication and was rescued by formate and extracellular nucleotides. These findings indicated that NDV replication relies on MTHFD2 to maintain nucleotide availability. Notably, nuclear MTHFD2 expression was increased during NDV infection and could represent a pathway by which NDV steals nucleotides from the nucleus. Collectively, these data reveal that NDV replication is regulated by the c-Myc-mediated 1C metabolic pathway and that the mechanism of nucleotide synthesis for viral replication is regulated by MTHFD2. Newcastle disease virus (NDV) is a dominant vector for vaccine and gene therapy that accommodates foreign genes well but can only infect mammalian cells that have undergone cancerous transformation. Understanding the remodeling of nucleotide metabolic pathways in host cells by NDV proliferation provides a new perspective for the precise use of NDV as a vector or in antiviral research. In this study, we demonstrated that NDV replication is strictly dependent on pathways involved in redox homeostasis in the nucleotide synthesis pathway, including the oxPPP and the mitochondrial one-carbon pathway. Further investigation revealed the potential involvement of NDV replication-dependent nucleotide availability in promoting MTHFD2 nuclear localization. Our findings highlight the differential dependence of NDV on enzymes for one-carbon metabolism, and the unique mechanism of action of MTHFD2 in viral replication, thereby providing a novel target for antiviral or oncolytic virus therapy.
Topics: Animals; Methylenetetrahydrofolate Dehydrogenase (NADP); Newcastle Disease; Newcastle disease virus; Nucleotides; Serine; Virus Replication; Cell Line; A549 Cells; Humans; Mesocricetus; Gene Knockdown Techniques; Protein Transport; Mitochondria; Up-Regulation
PubMed: 36794935
DOI: 10.1128/jvi.00016-23 -
Veterinary Medicine and Science Jan 2022Newcastle disease (ND) virus (NDV) is one of the major pathogens in poultry farms that causes severe economic damages to the poultry industry, especially broiler chicken...
BACKGROUND
Newcastle disease (ND) virus (NDV) is one of the major pathogens in poultry farms that causes severe economic damages to the poultry industry, especially broiler chicken and turkey farms. Despite the endemicity of ND and its many epidemics in the country, the nature of the Iranian strain of the Newcastle virus is still largely unknown. This study aimed to characterise and evaluate NDV isolates obtained from commercial poultry farms in Iran in 2019 through haemagglutinin-neuraminidase (HN) gene sequencing.
METHOD
HN gene of each NDV isolate was amplified and sequenced using specific primers followed by phylogenetic analysis of full length of HN gene open reading frame and amino acid (aa) sequence of HN.
RESULTS
Phylogenetic analysis of the HN gene showed that the virus is very closely related to genotypes VII and III. Analysis of HN gene nucleotide sequences showed that all isolates encode proteins with a length of 571 aa.
CONCLUSION
Results of the present study are useful for a better understanding of molecular epidemiology of indigenous NDV strains and determining important molecular differences between fields and commonly used vaccine strains related to main immunogenic proteins.
Topics: Animals; Chickens; Hemagglutinins; Iran; Neuraminidase; Newcastle Disease; Newcastle disease virus; Phylogeny; Poultry Diseases
PubMed: 34606181
DOI: 10.1002/vms3.629 -
International Journal of Molecular... May 2017Newcastle disease (ND) is one of the most important diseases of poultry worldwide. In the last decades, molecular research has gained a lot of new information about its... (Review)
Review
Newcastle disease (ND) is one of the most important diseases of poultry worldwide. In the last decades, molecular research has gained a lot of new information about its causative agent, (NDV). In poultry industry, certain strains of NDV have been used for preventive vaccination for more than 60 years. NDV has also been applied to cancer patients with beneficial effects for about 50 years, but this is less well known. The molecular basis for these differential effects of NDV in birds and man have been elucidated in the last decades and are explained in this review. The anti-neoplastic and immune-stimulatory properties in non-permissive hosts such as mouse and man have to do with the strong type I interferon responses induced in these foreign species. Additionally, NDV has the potential to break various types of tumor resistances and also to affect liver fibrosis. A main section is devoted to the benefits of clinical application of NDV and NDV-based vaccines to cancer patients. Reverse genetics technology allowed developing NDV into a vector suitable for gene therapy. Examples will be provided in which genetically engineered NDV is being used successfully as vector against new emerging viruses.
Topics: Adjuvants, Immunologic; Animals; Genetic Therapy; Genetic Vectors; Humans; Interferons; Mice; Neoplasms; Newcastle Disease; Newcastle disease virus; Oncolytic Virotherapy; Poultry; Poultry Diseases; Vaccination; Viral Vaccines
PubMed: 28531117
DOI: 10.3390/ijms18051103 -
BioMed Research International 2021Newcastle disease (ND) is a highly fatal, infectious, viral disease, and despite immunization with live and inactivated vaccines, the disease is still endemic, causing...
Newcastle disease (ND) is a highly fatal, infectious, viral disease, and despite immunization with live and inactivated vaccines, the disease is still endemic, causing heavy morbidity and mortality leading to huge economic losses to the poultry industry in Pakistan. Therefore, the present study was aimed for the first time in the country at using novel virosomal technology to develop the ND vaccine using an indigenous highly virulent strain of the virus. ND virosome was prepared using Triton X-100, and SM2 Bio-Beads were used to remove the detergent and reconstitute the viral membrane into virosome. Confirmation was done by transmission electron microscopy and protein analysis by SDS-PAGE. cell adhesion property was observed by incorporating green fluorescent protein (GFP), producing plasmid into virosome and cell culture assay. Sterility, safety, and stability of the vaccine were tested before evaluation of immunogenicity and challenge protection study in commercial broiler. The virosome vaccine was administered (30 g/bird) at days 7 and 14 through the intranasal route in comparison with commercially available live and inactivated ND vaccines. Results revealed significantly high ( < 0.05) and clinically protective hemagglutination inhibition (HI) antibody titers at 7, 14, 21, and 28 days postimmunization with the virosome vaccine in comparison to the negative control. The GMTs were comparable to live and inactivated vaccines with nonsignificant ( > 0.05) differences throughout the experiment. Antibody levels increased in all vaccinated groups gradually from the 7 day and were maximum at 28-day postvaccination. In the virosome-administered group, GMT was 83.18 and 77.62 at 21 and 28-days postvaccination, respectively. Challenge revealed 100%, 90%, and 80% protection in virosome, live, and inactivated vaccinated groups, respectively. Under given experimental conditions, we can conclude that ND virosome vaccine prepared from the indigenous virus was found to be safe and immunogenic.
Topics: Animals; Antibodies, Viral; Chickens; Newcastle Disease; Newcastle disease virus; Pakistan; Poultry Diseases; Vaccines, Virosome; Virosomes
PubMed: 33575353
DOI: 10.1155/2021/8879277 -
Poultry Science Jun 2023An immunization experiment was conducted in specific pathogen-free chickens with the inactivated Newcastle disease virus (NDV) vaccine encapsulated in the...
An immunization experiment was conducted in specific pathogen-free chickens with the inactivated Newcastle disease virus (NDV) vaccine encapsulated in the poly-(lactic-co-glycolic) acid (PLGA) nanoparticles (NP) to evaluate its immunogenicity and protective efficacy. The NDV vaccine was prepared by inactivating one virulent Indian strain of NDV belonging to Genotype VII by using beta-propiolactone. PLGA nanoparticles encapsulating inactivated NDV were prepared by the solvent evaporation method. Scanning electron microscopy and zeta sizer analysis revealed that the (PLGA+NDV) NP were spherical, with an average size of 300 nm, having a zeta potential of -6 mV. The encapsulation efficiency and loading efficiency were 72% and 2.4%, respectively. On immunization trial in chicken, the (PLGA+NDV) NP induced significantly (P < 0.0001) higher levels of HI and IgY antibodies with the peak HI titer of 2 and higher expression of IL-4 mRNA. The consistency of higher antibody levels suggests slow and pulsatile release of the antigens from the (PLGA+NDV) NP. The nano-NDV vaccine also induced cell mediated immunity with higher expression of IFN-γ indicating strong Th1 mediated immune responses in contrast to the commercial oil adjuvanted inactivated NDV vaccine. Further, the (PLGA+NDV) NP afforded 100% protection against the virulent NDV challenge. Our results suggested that PLGA NP have adjuvant potential on induction of humoral as well as Th1 biased cell mediated immune responses and also enhanced protective efficacy of the inactivated NDV vaccine. This study provides an insight for development of PLGA NP based inactivated NDV vaccine using the same genotype circulating in the field as well as for other avian diseases at exigencies.
Topics: Animals; Newcastle disease virus; Newcastle Disease; Chickens; Vaccines, Inactivated; Glycols; Adjuvants, Immunologic; Immunity, Cellular; Nanoparticles; Viral Vaccines
PubMed: 37116285
DOI: 10.1016/j.psj.2023.102679 -
Preventive Veterinary Medicine Nov 2018Bangladesh experiences some of the highest malnutrition rates in the world, and efforts are being made to increase food security and overall health status. One of the...
Bangladesh experiences some of the highest malnutrition rates in the world, and efforts are being made to increase food security and overall health status. One of the largest constrains on increasing food security is endemic diseases among livestock and poultry populations. Newcastle Disease (ND) is one of these viral endemic diseases reducing food security. However, the sero- and viro-prevalence of ND has not been thoroughly studied in rural poultry in Bangladesh. Knowledge of farm management practices and their effect on ND sero and viro-prevalence is needed before interventions can occur, and efforts to improve the endemic state of ND cannot begin without a baseline study. This cross-sectional study randomly sampled 129 rural households with 245 chickens for the sero-prevalence and active infection rate of rural chickens in two selected upazilas (sub-districts) of the Chittagong district. ELISA was used for the detection of sero-prevalence, and cloacal samples were analyzed for ND presence using one-step RT-PCR. The aims of this study were to describe farmer demography, determine the ND sero-prevalence at the household and individual chicken level, estimate the proportionate ND prevalence at the individual chicken level, determine potential risk factors for ND sero-prevalence at the household level, and determine challenges farmers face with household chicken farming. The overall household level ND sero-prevalence based on ELISA was 31.8% (41/129) (95% CI: 23.9-40.6%), whereas the overall bird level ND sero-prevalence based on ELISA was 21.2% (52/245) (95% CI: 16.5-26.8%). ND prevalence based on RT-PCR was 12.5% (4/32) (95% CI: 3.5-29.0%). The odds of ND sero-positivity was significantly higher in farms belonging to Rangunia than in farms belonging to Anowara with an odds ratio (OR) of 7.8 (95% CI: 3.3-18.6%). The odds of ND sero-positivity was significantly lower in poultry house cleaning frequency of once or twice weekly compared with once daily cleaning (OR = 0.3; 95% CI: 0.1-0.8%). High cleaning frequency may produce excessive stress on poultry predisposing them to infection. Poultry rearing is different between Anowara and Rangunia. Anowara (coastal) scavenging areas become restricted because of regular tide flow allowing small fishes and other aquatic animals to be the dominant scavengers in Anowara. The incoming tide also removes viral reservoirs such as feces and dead birds that may otherwise be readily accessed by healthy chickens.
Topics: Animal Husbandry; Animals; Bangladesh; Chickens; Cloaca; Enzyme-Linked Immunosorbent Assay; Housing, Animal; Newcastle Disease; Poultry Diseases; Prevalence; Seroepidemiologic Studies
PubMed: 30388994
DOI: 10.1016/j.prevetmed.2018.09.015 -
Veterinary Microbiology Jul 2017Newcastle disease (ND) has been defined by the World Organisation for Animal Health as infection of poultry with virulent strains of Newcastle disease virus (NDV).... (Review)
Review
Newcastle disease (ND) has been defined by the World Organisation for Animal Health as infection of poultry with virulent strains of Newcastle disease virus (NDV). Lesions affecting the neurological, gastrointestinal, respiratory, and reproductive systems are most often observed. The control of ND must include strict biosecurity that prevents virulent NDV from contacting poultry, and also proper administration of efficacious vaccines. When administered correctly to healthy birds, ND vaccines formulated with NDV of low virulence or viral-vectored vaccines that express the NDV fusion protein are able to prevent clinical disease and mortality in chickens upon infection with virulent NDV. Live and inactivated vaccines have been widely used since the 1950's. Recombinant and antigenically matched vaccines have been adopted recently in some countries, and many other vaccine approaches have been only evaluated experimentally. Despite decades of research and development towards formulation of an optimal ND vaccine, improvements are still needed. Impediments to prevent outbreaks include uneven vaccine application when using mass administration techniques in larger commercial settings, the difficulties associated with vaccinating free-roaming, multi-age birds of village flocks, and difficulties maintaining the cold chain to preserve the thermo-labile antigens in the vaccines. Incomplete or improper immunization often results in the disease and death of poultry after infection with virulent NDV. Another cause of decreased vaccine efficacy is the existence of antibodies (including maternal) in birds, which can neutralize the vaccine and thereby reduce the effectiveness of ND vaccines. In this review, a historical perspective, summary of the current situation for ND and NDV strains, and a review of traditional and experimental ND vaccines are presented.
Topics: Animals; Chickens; Newcastle Disease; Newcastle disease virus; Poultry; Poultry Diseases; Vaccination; Vaccines, Inactivated; Viral Vaccines
PubMed: 28024856
DOI: 10.1016/j.vetmic.2016.12.019 -
Veterinary Research Oct 2017Newcastle disease is caused by virulent strains of Newcastle disease virus (NDV), which causes substantial morbidity and mortality events worldwide in poultry. The virus... (Review)
Review
Newcastle disease is caused by virulent strains of Newcastle disease virus (NDV), which causes substantial morbidity and mortality events worldwide in poultry. The virus strains can be differentiated as lentogenic, mesogenic, or velogenic based on a mean death time in chicken embryos. Currently, velogenic strains of NDV are not endemic in United States domestic poultry; however, these strains are present in other countries and are occasionally detected in wild birds in the U.S. A viral introduction into domestic poultry could have severe economic consequences due to the loss of production from sick and dying birds, the cost of control measures such as depopulation and disinfection measures, and the trade restrictions that would likely be imposed as a result of an outbreak. Due to the disease-free status of the U.S. and the high cost of a potential viral incursion to the poultry industry, a qualitative risk analysis was performed to evaluate the vulnerabilities of the U.S. against the introduction of virulent strains of NDV. The most likely routes of virus introduction are explored and data gathered by several federal agencies is provided. Recommendations are ultimately provided for data that would be useful to further understand NDV on the landscape and to utilize all existing sampling opportunities to begin to comprehend viral movement and further characterize the risk of NDV introduction into the U.S.
Topics: Animals; Animals, Wild; Birds; Newcastle Disease; Newcastle disease virus; Poultry Diseases; Risk Assessment; United States; Virulence
PubMed: 29073919
DOI: 10.1186/s13567-017-0475-9 -
Frontiers in Immunology 2020Newcastle disease virus (NDV) infects poultry and antagonizes host immunity several mechanisms. Dendritic cells (DCs) are characterized as specialized antigen...
Newcastle disease virus (NDV) infects poultry and antagonizes host immunity several mechanisms. Dendritic cells (DCs) are characterized as specialized antigen presenting cells, bridging innate and adaptive immunity and regulating host resistance to viral invasion. However, there is little specific knowledge of the role of DCs in NDV infection. In this study, the representative NDV lentogenic strain LaSota was used to explore whether murine bone marrow derived DCs mature following infection. We examined surface molecule expression and cytokine release from DCs as well as proliferation and activation of T cells and in the context of NDV. The results demonstrated that infection with lentogenic strain LaSota induced a phenotypic maturation of immature DCs (imDCs), which actually led to curtailed T cell responses. Upon infection, the phenotypic maturation of DCs was reflected by markedly enhanced MHC and costimulatory molecule expression and secretion of proinflammatory cytokines. Nevertheless, NDV-infected DCs produced the anti-inflammatory cytokine IL-10 and attenuated T cell proliferation, inducing Th2-biased responses. Therefore, our study reveals a novel understanding that DCs are phenotypically mature but dysfunctional in priming T cell responses during NDV infection.
Topics: Animals; Cell Proliferation; Chick Embryo; Dendritic Cells; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Newcastle Disease; Newcastle disease virus; T-Lymphocytes
PubMed: 33708193
DOI: 10.3389/fimmu.2020.619829 -
Journal of Virology May 2023vaccination is an attractive immunization approach for chickens. However, most live Newcastle disease virus (NDV) vaccine strains used safely after hatching are unsafe...
vaccination is an attractive immunization approach for chickens. However, most live Newcastle disease virus (NDV) vaccine strains used safely after hatching are unsafe as vaccines due to their high pathogenicity for chicken embryos. The mechanism for viral pathogenicity in chicken embryos is poorly understood. Our previous studies reported that NDV strain TS09-C was a safe vaccine, and the F protein cleavage site (FCS) containing three basic amino acids (3B-FCS) was the crucial determinant of the attenuation of TS09-C in chicken embryos. Here, five trypsin-like proteases that activated NDV in chicken embryos were identified. The F protein with 3B-FCS was sensitive to the proteases Tmprss4, Tmprss9, and F7, was present in fewer tissue cells of chicken embryos, which limited the viral tropism, and was responsible for the attenuation of NDV with 3B-FCS, while the F protein with FCS containing two basic amino acids could be cleaved not only by Tmprss4, Tmprss9, and F7 but also by Prss23 and Cfd, was present in most tissue cells, and thereby was responsible for broad tissue tropism and high pathogenicity of virus in chicken embryos. Furthermore, when mixed with the protease inhibitors aprotinin and camostat, NDV with 2B-FCS exhibited greatly weakened pathogenicity in chicken embryos. Thus, our results extend the understanding of the molecular mechanism of NDV pathogenicity in chicken embryos and provide a novel molecular target for the rational design of vaccines, ensuring uniform and effective vaccine delivery and earlier induction of immune protection by the time of hatching. As an attractive immunization approach for chickens, vaccination can induce a considerable degree of protection by the time of hatching, provide support in closing the window in which birds are susceptible to infection, facilitate fast and uniform vaccine delivery, and reduce labor costs by the use of mechanized injectors. The commercial live Newcastle disease virus (NDV) vaccine strains are not safe for vaccination and cause the death of chicken embryos. The mechanism for viral pathogenicity in chicken embryos is poorly understood. In the present study, we identified five trypsin-like proteases that activate NDV in chicken embryos and elucidated their roles in the tissue tropism and pathogenicity of NDV used as vaccine. Finally, we revealed the molecular basis for the pathogenicity of NDV in chicken embryos and provided a novel strategy for the rational design of ND vaccines.
Topics: Animals; Chick Embryo; Antibodies, Viral; Chickens; Newcastle Disease; Newcastle disease virus; Peptide Hydrolases; Poultry Diseases; Vaccines, Attenuated; Viral Vaccines; Virulence
PubMed: 37042750
DOI: 10.1128/jvi.00324-23