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1
Marc, Daniel. "Influenza virus non-structural protein NS1: interferon antagonism and beyond." Journal of General Virology 95, no. 12 (December 1, 2014): 2594–611. http://dx.doi.org/10.1099/vir.0.069542-0.
Full textAbstract:
Most viruses express one or several proteins that counter the antiviral defences of the host cell. This is the task of non-structural protein NS1 in influenza viruses. Absent in the viral particle, but highly expressed in the infected cell, NS1 dramatically inhibits cellular gene expression and prevents the activation of key players in the IFN system. In addition, NS1 selectively enhances the translation of viral mRNAs and may regulate the synthesis of viral RNAs. Our knowledge of the virus and of NS1 has increased dramatically during the last 15 years. The atomic structure of NS1 has been determined, many cellular partners have been identified and its multiple activities have been studied in depth. This review presents our current knowledge, and attempts to establish relationships between the RNA sequence, the structure of the protein, its ligands, its activities and the pathogenicity of the virus. A better understanding of NS1 could help in elaborating novel antiviral strategies, based on either live vaccines with altered NS1 or on small-compound inhibitors of NS1.
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Beddingfield, Brandon J., Jessica N. Hartnett, Russell B. Wilson, Peter C. Kulakosky, Kristian G. Andersen, Refugio Robles-Sikisaka, Nathan D. Grubaugh, et al. "Zika Virus Non-Structural Protein 1 Antigen-Capture Immunoassay." Viruses 13, no. 9 (September 5, 2021): 1771. http://dx.doi.org/10.3390/v13091771.
Full textAbstract:
Infection with Zika virus (ZIKV), a member of the Flavivirus genus of the Flaviviridae family, typically results in mild self-limited illness, but severe neurological disease occurs in a limited subset of patients. In contrast, serious outcomes commonly occur in pregnancy that affect the developing fetus, including microcephaly and other major birth defects. The genetic similarity of ZIKV to other widespread flaviviruses, such as dengue virus (DENV), presents a challenge to the development of specific ZIKV diagnostic assays. Nonstructural protein 1 (NS1) is established for use in immunodiagnostic assays for flaviviruses. To address the cross-reactivity of ZIKV NS1 with proteins from other flaviviruses we used site-directed mutagenesis to modify putative epitopes. Goat polyclonal antibodies to variant ZIKV NS1 were affinity-purified to remove antibodies binding to the closely related NS1 protein of DENV. An antigen-capture ELISA configured with the affinity-purified polyclonal antibody showed a linear dynamic range between approximately 500 and 30 ng/mL, with a limit of detection of between 1.95 and 7.8 ng/mL. NS1 proteins from DENV, yellow fever virus, St. Louis encephalitis virus and West Nile virus showed significantly reduced reactivity in the ZIKV antigen-capture ELISA. Refinement of approaches similar to those employed here could lead to development of ZIKV-specific immunoassays suitable for use in areas where infections with related flaviviruses are common.
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Sankar, S. Gowri, K. J. Dhanajeyan, R. Paramasivan, V. Thenmozhi, B. K. Tyagi, and S. John Vennison. "High-Level Expression of Functionally Active Dengue-2 Non-Structural Antigen 1 Production inEscherichia coli." BioMed Research International 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/343195.
Full textAbstract:
Detection of nonstructural protein (NS1) is an important diagnostic marker during acute phase of dengue infection. Not only for diagnostic purpose, the protein had important role in vaccine design as well, as a candidate for studying virus assembly and maturation. Various researchers employed different expression systems and strategies for recombinant NS1 protein production. Attempts to express NS1 protein in prokaryotic and yeast expression system result in formation of insoluble protein which needs to undergo refolding to attain native structural and functional forms. Here, we report the production of soluble NS1 protein inE. coliby using appropriate vector and employing suitable culture conditions to maximize protein production. Proteins were purified using metal affinity chromatography. SDS-PAGE and western blot analysis reveal the native structure of NS1 protein. Solid phase ELISA using the recombinantly expressed antigen with positive and negative dengue samples showed that the expressed protein retains its antigenic and immunological properties. To our knowledge, this is the first report on the successful production of functionally active recombinant dengue-2 NS1 protein production without undergoing anyin vitroposttranslational modification process.
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Wan, Shu-Wen, Miao-Huei Cheng, and Yan-Hua Lee. "Rab27-dependent extracellular vesicle releasing participates in dengue virus non-structural protein 1 secretion." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 236.04. http://dx.doi.org/10.4049/jimmunol.210.supp.236.04.
Full textAbstract:
Abstract Dengue disease is one of important arthropod-borne disease in the world and causes around 20,000 deaths annually. Dengue virus (DENV) non-structural protein 1 (NS1) is the major secreted non-structural protein from infected cells and highly associated with the pathogenesis of severe dengue. Several studies have shown that the secreted NS1 contribute to increase of vascular permeability, coagulopathy, activation of immune cells as well as inflammation. These findings strongly indicate the pathological roles of secreted NS1; however, the secretory pathway is not fully clear. Accumulating evidence have shown that virus-associated extracellular vesicles (EVs) not only contain viral components including viral proteins, genetic material or virion particle but also host components. Rab27 is one of several GTPases essential to regulate EV releasing by affecting docking of multivesicular body (MVB) to the target plasma membrane. Here, we show that NS1 can be exported from DENV-infected cells by EVs. NS1 as well as EV biogenesis-associated proteins ALG-2-interacting protein X (ALIX) and neutral sphingomyelinase2 (nSMase2) co-accumulate in extracellular vesicles. We next determine the topology of NS1 and demonstrate that NS1 is associated at the surface of EVs. In addition, the secretion of DENV NS1 is regulated by Rab27. The EV biogenesis and secretion inhibitor, Tipifarnib treatment decreases the levels of NS1 and nSMase 2 but not the levels of ALIX in the EVs. Taken together, this study not only provide the new insights of mechanisms in DENV NS1 secretion through Rab27-mediated vesicle trafficking but also valuable therapeutic targets to dengue disease. Supported by grants from Ministry of Science and Technology of Taiwan (MOST 111-2320-B-006 -051 -MY3)
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Susilowati Andajani. "Structural Non-Structural Protein-1 Virus Dengue of Risk Factors on Functional Interference Hepar." Medico Legal Update 20, no. 2 (May 22, 2020): 796–800. http://dx.doi.org/10.37506/mlu.v20i2.1213.
Full textAbstract:
The causes of hepatic damage to DHF are mixed. Dengue virus can infect the liver and cause damage.Histopathology of the liver in cases of fatal dengue shows that hepatocytes and Kupffer cells can be thetarget of viral replication and there is involvement of apoptotic mechanism. This study aims to determinethe association between dengue virus NS1 protein and degree of clinical manifestation of dengue infectionwith hepatic dysfunction. Blood samples after taking the serum, were examined for dengue virus NS1protein and SGOT and SGPT examinations at the Surabaya Health Laboratory Center. Data analysis usedChi Square, Fisher's Exact, Anava and Dunnet (a = 0.05). The results shows that the correlated variablesignificantly with dengue hemorrhagic manifestation degree was dengue virus NS protein1 (p = 0.047),with correlation strength of 26.8%. Variables significantly correlated with liver dysfunction were degreeof clinical manifestation of dengue fever (p = 0.037) with correlation strength of 33.5% and dengue virusNS protein1 (p = 0.023) with correlation strength of 29.3%. There was a significant relationship betweenthe presence of dengue virus NS1 protein and the incidence of DHF. There was a significant relationshipbetween the presence of dengue virus NS1 protein with hepatic dysfunction (SGOT and SGPT) in denguevirus infection.
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Warner, Nikole L., Susan B. Core, and Kathryn M. Frietze. "Unbiased Identification of Dengue Virus Non-Structural Protein 1 Peptides for Use in Vaccine Design." Vaccines 10, no. 12 (November 27, 2022): 2028. http://dx.doi.org/10.3390/vaccines10122028.
Full textAbstract:
Dengue virus (DENV) is a global health problem, with over half of the world’s population at risk for infection. Despite this, there is only one licensed vaccine available to prevent infection and safety concerns limit immunization to only a subset of individuals. Most dengue virus vaccine efforts attempt to evoke broadly neutralizing antibodies against structural proteins. However, eliciting antibodies to block the activity of viral proteins involved in pathogenesis could be a useful complementary approach. Studies suggest that non-structural protein 1, which participates in disruption of the endothelial barrier and is hypothesized to play a significant role in the progression to severe dengue, could be a promising target for vaccine efforts. Here, we used an unbiased approach to identify peptide epitopes of dengue virus non-structural protein 1 that could evoke antibodies that bind to NS1 from all 4 serotypes and also bind to DENV-infected cells. DENV-2 NS1 peptides were generated such that 35 overlapping 15 amino acid peptides represented the entire NS1 protein. These peptides were each chemically conjugated to bacteriophage virus-like particles (VLP) and used to immunize mice. Sera were then screened for IgG to cognate peptide as well as binding to recombinant hexameric NS1 from all four DENV serotypes as well as binding to DENV-2 infected cells by microscopy. From these data, we identified several peptides that were able to elicit antibodies that could bind to infected cells as well as DENV NS1. These peptides and their homologues in the corresponding NS1 of other DENV serotypes could be used as potential immunogens to elicit binding antibodies to NS1. Future studies will investigate the functional and protective capacities of antibodies elicited by these immunogens against DENV NS1.
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Cunha, Andreia E. S., Rui J. S. Loureiro, Carlos J. V. Simões, and Rui M. M. Brito. "Unveiling New Druggable Pockets in Influenza Non-Structural Protein 1: NS1–Host Interactions as Antiviral Targets for Flu." International Journal of Molecular Sciences 24, no. 3 (February 3, 2023): 2977. http://dx.doi.org/10.3390/ijms24032977.
Full textAbstract:
Influenza viruses are responsible for significant morbidity and mortality worldwide in winter seasonal outbreaks and in flu pandemics. Influenza viruses have a high rate of evolution, requiring annual vaccine updates and severely diminishing the effectiveness of the available antivirals. Identifying novel viral targets and developing new effective antivirals is an urgent need. One of the most promising new targets for influenza antiviral therapy is non-structural protein 1 (NS1), a highly conserved protein exclusively expressed in virus-infected cells that mediates essential functions in virus replication and pathogenesis. Interaction of NS1 with the host proteins PI3K and TRIM25 is paramount for NS1’s role in infection and pathogenesis by promoting viral replication through the inhibition of apoptosis and suppressing interferon production, respectively. We, therefore, conducted an analysis of the druggability of this viral protein by performing molecular dynamics simulations on full-length NS1 coupled with ligand pocket detection. We identified several druggable pockets that are partially conserved throughout most of the simulation time. Moreover, we found out that some of these druggable pockets co-localize with the most stable binding regions of the protein–protein interaction (PPI) sites of NS1 with PI3K and TRIM25, which suggests that these NS1 druggable pockets are promising new targets for antiviral development.
8
Rahim, Md, Ludger Klewes, Ali Zahedi-Amiri, Sabine Mai, and Kevin Coombs. "Global Interactomics Connect Nuclear Mitotic Apparatus Protein NUMA1 to Influenza Virus Maturation." Viruses 10, no. 12 (December 19, 2018): 731. http://dx.doi.org/10.3390/v10120731.
Full textAbstract:
Influenza A virus (IAV) infections remain a major human health threat. IAV has enormous genetic plasticity and can rapidly escape virus-targeted anti-viral strategies. Thus, there is increasing interest to identify host proteins and processes the virus requires for replication and maturation. The IAV non-structural protein 1 (NS1) is a critical multifunctional protein that is expressed to high levels in infected cells. Host proteins that interact with NS1 may serve as ideal targets for attenuating IAV replication. We previously developed and characterized broadly cross-reactive anti-NS1 monoclonal antibodies. For the current study, we used these mAbs to co-immunoprecipitate native IAV NS1 and interacting host proteins; 183 proteins were consistently identified in this NS1 interactome study, 124 of which have not been previously reported. RNAi screens identified 11 NS1-interacting host factors as vital for IAV replication. Knocking down one of these, nuclear mitotic apparatus protein 1 (NUMA1), dramatically reduced IAV replication. IAV genomic transcription and translation were not inhibited but transport of viral structural proteins to the cell membrane was hindered during maturation steps in NUMA1 knockdown (KD) cells.
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Dubrow, Alyssa, Sirong Lin, Nowlan Savage, Qingliang Shen, and Jae-Hyun Cho. "Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK." Viruses 12, no. 3 (March 20, 2020): 338. http://dx.doi.org/10.3390/v12030338.
Full textAbstract:
The 1918 influenza A virus (IAV) caused the worst flu pandemic in human history. Non-structural protein 1 (NS1) is an important virulence factor of the 1918 IAV and antagonizes host antiviral immune responses. NS1 increases virulence by activating phosphoinositide 3-kinase (PI3K) via binding to the p85β subunit of PI3K. Intriguingly, unlike the NS1 of other human IAV strains, 1918 NS1 hijacks another host protein, CRK, to form a ternary complex with p85β, resulting in hyperactivation of PI3K. However, the molecular basis of the ternary interaction between 1918 NS1, CRK, and PI3K remains elusive. Here, we report the structural and thermodynamic bases of the ternary interaction. We find that the C-terminal tail (CTT) of 1918 NS1 remains highly flexible in the complex with p85β. Thus, the CTT of 1918 NS1 in the complex with PI3K can efficiently hijack CRK. Notably, our study indicates that 1918 NS1 enhances its affinity to p85β in the presence of CRK, which might result in enhanced activation of PI3K. Our results provide structural insight into how 1918 NS1 hijacks two host proteins simultaneously.
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Asyura, Muhammad Mikail Athif Zhafir, Ahmad Fauzi, and Fakhru Adlan Ayub. "Potential of Peptide-Based Non-Structural Protein 1 (NS1) Inhibitor in Obstructing Dengue Virus (DENV) Replication." Green Medical Journal 3, no. 1 (April 29, 2021): 1–12. http://dx.doi.org/10.33096/gmj.v3i1.71.
Full textAbstract:
Introduction: Dengue Virus (DENV) is the pathogen for human dengue fever and is responsible for 390 million infections per year. The viral genome produces about 10 viral protein products, one of them being NS1. The NS1 protein plays a key role in viral replication and stimulation of humoral immune cells, thus being the perfect candidate to create an effective antiviral drug or vaccine for dengue
Methods: Dengue Virus (DENV) is the pathogen for human dengue fever and is responsible for 390 million infections per year. The viral genome produces about 10 viral protein products, one of them being NS1. The NS1 protein plays a key role in viral replication and stimulation of humoral immune cells, thus being the perfect candidate to create an effective antiviral drug or vaccine for dengue
Conclusion: The review established promising results of using peptide-based intervention on NS1. Further in vivo and randomized controlled trials are advised to solidify the applicability and biosafety of the intervention
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Warner, Nikole L., and Kathryn M. Frietze. "Development of Bacteriophage Virus-Like Particle Vaccines Displaying Conserved Epitopes of Dengue Virus Non-Structural Protein 1." Vaccines 9, no. 7 (July 2, 2021): 726. http://dx.doi.org/10.3390/vaccines9070726.
Full textAbstract:
Dengue virus (DENV) is a major global health problem, with over half of the world’s population at risk of infection. Despite over 60 years of efforts, no licensed vaccine suitable for population-based immunization against DENV is available. Here, we describe efforts to engineer epitope-based vaccines against DENV non-structural protein 1 (NS1). NS1 is present in DENV-infected cells as well as secreted into the blood of infected individuals. NS1 causes disruption of endothelial cell barriers, resulting in plasma leakage and hemorrhage. Immunizing against NS1 could elicit antibodies that block NS1 function and also target NS1-infected cells for antibody-dependent cell cytotoxicity. We identified highly conserved regions of NS1 from all four DENV serotypes. We generated synthetic peptides to these regions and chemically conjugated them to bacteriophage Qβ virus-like particles (VLPs). Mice were immunized two times with the candidate vaccines and sera were tested for the presence of antibodies that bound to the cognate peptide, recombinant NS1 from all four DENV serotypes, and DENV-2-infected cells. We found that two of the candidate vaccines elicited antibodies that bound to recombinant NS1, and one candidate vaccine elicited antibodies that bound to DENV-infected cells. These results show that an epitope-specific vaccine against conserved regions of NS1 could be a promising approach for DENV vaccines or therapeutics to bind circulating NS1 protein.
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Hale, Benjamin G., Richard E. Randall, Juan Ortín, and David Jackson. "The multifunctional NS1 protein of influenza A viruses." Journal of General Virology 89, no. 10 (October 1, 2008): 2359–76. http://dx.doi.org/10.1099/vir.0.2008/004606-0.
Full textAbstract:
The non-structural (NS1) protein of influenza A viruses is a non-essential virulence factor that has multiple accessory functions during viral infection. In recent years, the major role ascribed to NS1 has been its inhibition of host immune responses, especially the limitation of both interferon (IFN) production and the antiviral effects of IFN-induced proteins, such as dsRNA-dependent protein kinase R (PKR) and 2'5'-oligoadenylate synthetase (OAS)/RNase L. However, it is clear that NS1 also acts directly to modulate other important aspects of the virus replication cycle, including viral RNA replication, viral protein synthesis, and general host-cell physiology. Here, we review the current literature on this remarkably multifunctional viral protein. In the first part of this article, we summarize the basic biochemistry of NS1, in particular its synthesis, structure, and intracellular localization. We then discuss the various roles NS1 has in regulating viral replication mechanisms, host innate/adaptive immune responses, and cellular signalling pathways. We focus on the NS1–RNA and NS1–protein interactions that are fundamental to these processes, and highlight apparent strain-specific ways in which different NS1 proteins may act. In this regard, the contributions of certain NS1 functions to the pathogenicity of human and animal influenza A viruses are also discussed. Finally, we outline practical applications that future studies on NS1 may lead to, including the rational design and manufacture of influenza vaccines, the development of novel antiviral drugs, and the use of oncolytic influenza A viruses as potential anti-cancer agents.
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Hale, Benjamin G. "Conformational plasticity of the influenza A virus NS1 protein." Journal of General Virology 95, no. 10 (October 1, 2014): 2099–105. http://dx.doi.org/10.1099/vir.0.066282-0.
Full textAbstract:
During infection, the influenza A virus non-structural protein 1 (NS1) interacts with a diverse range of viral and cellular factors to antagonize host antiviral defences and promote viral replication. Here, I review the structural basis for some of these functions and discuss the emerging view that NS1 cannot simply be regarded as a ‘static’ protein with a single structure. Rather, the dynamic property of NS1 to adopt various quaternary conformations is critical for its multiple activities. Understanding NS1 plasticity, and the mechanisms governing this plasticity, will be essential for assessing both fundamental protein function and the consequences of strain-dependent polymorphisms in this important virulence factor.
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Li, Wei, James W. Noah, and Diana L. Noah. "Alanine substitutions within a linker region of the influenza A virus non-structural protein 1 alter its subcellular localization and attenuate virus replication." Journal of General Virology 92, no. 8 (August 1, 2011): 1832–42. http://dx.doi.org/10.1099/vir.0.031336-0.
Full textAbstract:
The influenza A virus non-structural protein 1 (NS1) is a multifunctional protein and an important virulence factor. It is composed of two well-characterized domains linked by a short, but not well crystallographically defined, region of unknown function. To study the possible function of this region, we introduced alanine substitutions to replace the two highly conserved leucine residues at amino acid positions 69 and 77. The mutant L69,77A NS1 protein retained wild-type (WT)-comparable binding capabilities to dsRNA, cleavage and polyadenylation specificity factor 30 and the p85β subunit of PI3K. A mutant influenza A virus expressing the L69,77A NS1 protein was generated using reverse genetics. L69,77A NS1 virus infection induced significantly higher levels of beta interferon (IFN-β) expression in Madin–Darby canine kidney (MDCK) cells compared with WT NS1 virus. In addition, the replication rate of the L69,77A NS1 virus was substantially lower in MDCK cells but not in Vero cells compared with the WT virus, suggesting that the L69,77A NS1 protein does not fully antagonize IFN during viral replication. L69,77A NS1 virus infection was not able to activate the PI3K/Akt anti-apoptotic pathway, suggesting that the mutant NS1 protein may not be localized such that it has access to p85β in vivo during infection, which was supported by the altered subcellular localization pattern of the mutant NS1 compared with WT NS1 after transfection or virus infection. Our data demonstrate that this linker region between the two domains is critical for the functions of the NS1 protein during influenza A virus infection, possibly by determining the protein’s correct subcellular localization.
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Arodes, Evy Suryani, Beti Ernawati Dewi, and Tjahjani Mirawati Sudiro. "Horseradish peroxidase-labeled rabbit anti-non-structural protein 1 of dengue virus-2 for the diagnosis of dengue virus infections." Medical Journal of Indonesia 28, no. 2 (August 9, 2019): 103–9. http://dx.doi.org/10.13181/mji.v28i2.1951.
Full textAbstract:
BACKGROUND Early diagnosis of dengue virus (DENV) infection is essential for patient management and disease control. Detection of the antigen non-structural protein 1 (NS1) has been proven to provide early diagnosis of DENV infection. Thus, commercial NS1 antigen detection assays have been increasingly used and are becoming thetool of choice among clinicians to confirm DENV infection in Indonesia.
METHODS To obtain anti-NS1 DENV antibody, NS1 protein (90 µg/ml) from the collection of the Department of Microbiology, Faculty of Medicine, Universitas Indonesia was injected into a rabbit. The anti-NS1 antibody from the rabbit was then labeled with horseradish peroxidase (HRP) using the periodate oxidation method. Sera were tested by enzyme-linked immunosorbent assay (ELISA) to detect NS1 from DENV-infected patients.
RESULTS Serially diluted antibody labeled with HRP tested using the direct ELISA method showed the highest absorbance value at a 1:100 dilution (Mean [SD] = 1.35 [0.35]); even at a dilution as high as 1:3,200 (0.22 [0.15]), antibody labeled with HRP was able to detect the NS1 protein, although the absorbance value did not differ greatly from that of the negative control (0.13 [0.01]).
CONCLUSIONS In an attempt to develop an NS1-based diagnostic test, polyclonal anti-NS1 DENV antibody was successfully produced as a diagnostic assay to determine the presence of DENV NS1 antigen in patients’ sera.
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Salat, Jiri, Kamil Mikulasek, Osmany Larralde, Petra Pokorna Formanova, Ales Chrdle, Jan Haviernik, Jana Elsterova, et al. "Tick-Borne Encephalitis Virus Vaccines Contain Non-Structural Protein 1 Antigen and May Elicit NS1-Specific Antibody Responses in Vaccinated Individuals." Vaccines 8, no. 1 (February 12, 2020): 81. http://dx.doi.org/10.3390/vaccines8010081.
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Vaccination against tick-borne encephalitis (TBE) is based on the use of formalin-inactivated, culture-derived whole-virus vaccines. Immune response following vaccination is primarily directed to the viral envelope (E) protein, the major viral surface antigen. In Europe, two TBE vaccines are available in adult and pediatric formulations, namely FSME-IMMUN® (Pfizer) and Encepur® (GlaxoSmithKline). Herein, we analyzed the content of these vaccines using mass spectrometry (MS). The MS analysis revealed that the Encepur vaccine contains not only proteins of the whole virus particle, but also viral non-structural protein 1 (NS1). MS analysis of the FSME-IMMUN vaccine failed due to the high content of human serum albumin used as a stabilizer in the vaccine. However, the presence of NS1 in FSME-IMMUN was confirmed by immunization of mice with six doses of this vaccine, which led to a robust anti-NS1 antibody response. NS1-specific Western blot analysis also detected anti-NS1 antibodies in sera of humans who received multiple doses of either of these two vaccines; however, most vaccinees who received ≤3 doses were negative for NS1-specific antibodies. The contribution of NS1-specific antibodies to protection against TBE was demonstrated by immunization of mice with purified NS1 antigen, which led to a significant (p < 0.01) prolongation of the mean survival time after lethal virus challenge. This indicates that stimulation of anti-NS1 immunity by the TBE vaccines may increase their protective effect.
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Wong, Marcus P., Scott B. Biering, David L. Akey, Nicholas TN Lo, W. Clay Brown, Francielle Tramontini Gomes de Sousa, Henry Puerta-Guardo, et al. "Characterization of a protective antibody against dengue virus non-structural protein 1 (NS1) reveals critical domains required for NS1-triggered pathogenesis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 167.23. http://dx.doi.org/10.4049/jimmunol.204.supp.167.23.
Full textAbstract:
Abstract Dengue virus (DENV) is a medically important, mosquito-borne flavivirus that infects up to 390 million people annually. A signature of severe DENV infection is vascular leak, which can lead to shock and organ failure. We and others have shown that secreted DENV non-structural protein 1 (NS1) triggers endothelial cell (EC) hyperpermeability and vascular leak. Antibodies (Abs) targeting NS1 prevent NS1-induced EC hyperpermeability in vitro and are protective against lethal DENV challenge, as shown by vaccination of mice against NS1 and passive transfer of α-NS1 polyclonal serum. How α-NS1 Abs protect against pathogenesis, however, remains obscure. Here we characterize possible mechanisms behind the protective ability of an NS1-specific monoclonal Ab, 2B7. We show that 2B7 abrogates NS1 binding to ECs and EC hyperpermeability in vitro and inhibits vascular leak and mortality in vivo. Guided by crystal structures of NS1 complexed to a 2B7 Fab fragment, we mutated the amino acids on NS1 that comprise the NS1:2B7 interface. Intriguingly, while these contact sites were critical for the interaction between 2B7 and NS1, they were dispensable for NS1:EC binding. The structures and mutagenesis results suggest that 2B7 abrogates NS1 binding indirectly by sterically hindering the binding domain on NS1 from interacting with ECs. The mutagenesis also identified a key residue on NS1 that is necessary for inducing EC hyperpermeability without affecting NS1:EC binding, suggesting that 2B7 may also block an additional step in NS1 pathogenesis. This work provides mechanistic insight into the blockade of DENV NS1-mediated pathogenesis by α-NS1 Abs and identifies critical domains that serve as targets for drugs and vaccine-induced α-NS1 Ab responses.
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Naceri, Sarah, Daniel Marc, Anne-Claude Camproux, and Delphine Flatters. "Influenza A Virus NS1 Protein Structural Flexibility Analysis According to Its Structural Polymorphism Using Computational Approaches." International Journal of Molecular Sciences 23, no. 3 (February 4, 2022): 1805. http://dx.doi.org/10.3390/ijms23031805.
Full textAbstract:
Influenza A viruses are highly contagious RNA viruses that cause respiratory tract infections in humans and animals. Their non-structural protein NS1, a homodimer of two 230-residue chains, is the main viral factor in counteracting the antiviral defenses of the host cell. Its RNA-binding domain is an obligate dimer that is connected to each of the two effector domains by a highly flexible unstructured linker region of ten amino acids. The flexibility of NS1 is a key property that allows its effector domains and its RNA binding domain to interact with several protein partners or RNAs. The three-dimensional structures of full-length NS1 dimers revealed that the effector domains could adopt three distinct conformations as regards their mutual interactions and their orientation relative to the RNA binding domain (closed, semi-open and open). The origin of this structural polymorphism is currently being investigated and several hypotheses are proposed, among which one posits that it is a strain-specific property. In the present study, we explored through computational molecular modeling the dynamic and flexibility properties of NS1 from three important influenza virus A strains belonging to three distinct subtypes (H1N1, H6N6, H5N1), for which at least one conformation is available in the Protein Data Bank. In order to verify whether NS1 is stable in three forms for the three strains, we constructed homology models if the corresponding forms were not available in the Protein Data Bank. Molecular dynamics simulations were performed in order to predict the stability over time of the three distinct sequence variants of NS1, in each of their three distinct conformations. Our results favor the co-existence of three stable structural forms, regardless of the strain, but also suggest that the length of the linker, along with the presence of specific amino acids, modulate the dynamic properties and the flexibility of NS1.
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Takamatsu, Yuki, Kenta Okamoto, Duc Tuan Dinh, Fuxun Yu, Daisuke Hayasaka, Leo Uchida, Takeshi Nabeshima, Corazon C. Buerano, and Kouichi Morita. "NS1′ protein expression facilitates production of Japanese encephalitis virus in avian cells and embryonated chicken eggs." Journal of General Virology 95, no. 2 (February 1, 2014): 373–83. http://dx.doi.org/10.1099/vir.0.057968-0.
Full textAbstract:
Japanese encephalitis virus (JEV), which belongs to the genus Flavivirus of the family Flaviviridae, is a leading cause of meningo-encephalitis in Asian countries. The flavivirus non-structural protein 1 (NS1) plays a role in virus replication and in the elicitation of an immune response. The NS1′ protein found among the members of the JEV subgroup is an extended form of NS1 and is generated by a −1 ribosomal frameshift. This protein is known to be involved in viral pathogenicity; however, its specific function is still unknown. Here, we describe an investigation of the molecular function of NS1′ protein through the production of JEV NS1′-expressing and -non-expressing clones and their infection of avian and mammalian cells. Efficient NS1′ protein expression was observed in avian cells and was found to facilitate JEV production in both avian cultured cells and embryonated chicken eggs. NS1′ protein was observed to co-localize with NS5 protein and resulted in increased viral RNA levels in avian cells. These findings clearly indicate that NS1′ enhances the production of JEV in avian cells and may facilitate the amplification/maintenance role of birds in the virus transmission cycle in nature.
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Stiasny, Karin, Agnes Leitner, Heidemarie Holzmann, and Franz X. Heinz. "Dynamics and Extent of Non-Structural Protein 1-Antibody Responses in Tick-Borne Encephalitis Vaccination Breakthroughs and Unvaccinated Patients." Viruses 13, no. 6 (May 27, 2021): 1007. http://dx.doi.org/10.3390/v13061007.
Full textAbstract:
Tick-borne encephalitis (TBE) has a substantial impact on human public health in many parts of Europe and Asia. Effective inactivated purified whole-virus vaccines are in widespread use in TBE-endemic countries. Nevertheless, vaccination breakthroughs (VBTs) with manifest clinical disease do occur, and their specific serodiagnosis was shown to be facilitated by the detection of antibodies to a non-structural protein (NS1) that is produced during virus replication. However, recent data have shown that NS1 is also present in the current inactivated vaccines, with the potential of inducing corresponding antibodies and obscuring a proper interpretation of NS1-antibody assays for diagnosing VBTs. In our study, we quantified anti-virion and anti-NS1 antibody responses after vaccination as well as after natural infection in TBE patients, both without and with a history of previous TBE vaccination (VBTs). We did not find significant levels of NS1-specific antibodies in serum samples from 48 vaccinees with a completed vaccination schedule. In contrast, all TBE patients mounted an anti-NS1 antibody response, irrespective of whether they were vaccinated or not. Neither the dynamics nor the extent of NS1-antibody formation differed significantly between the two cohorts, arguing against substantial NS1-specific priming and an anamnestic NS1-antibody response in VBTs.
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Yang, Bo, Jiamin Zhang, Dawei Cai, Doulin Li, Wuguo Chen, Hong Jiang, and Yuanyang Hu. "Biochemical characterization of Periplaneta fuliginosa densovirus non-structural protein NS1." Biochemical and Biophysical Research Communications 342, no. 4 (April 2006): 1188–96. http://dx.doi.org/10.1016/j.bbrc.2006.02.053.
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Jia, Danlin, Ramtin Rahbar, Renee W. Y. Chan, Suki M. Y. Lee, Michael C. W. Chan, Ben Xuhao Wang, Darren P. Baker, et al. "Influenza Virus Non-Structural Protein 1 (NS1) Disrupts Interferon Signaling." PLoS ONE 5, no. 11 (November 10, 2010): e13927. http://dx.doi.org/10.1371/journal.pone.0013927.
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Blake, Morgan E., Alex B. Kleinpeter, Alexander S. Jureka, and Chad M. Petit. "Structural Investigations of Interactions between the Influenza a Virus NS1 and Host Cellular Proteins." Viruses 15, no. 10 (October 7, 2023): 2063. http://dx.doi.org/10.3390/v15102063.
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The Influenza A virus is a continuous threat to public health that causes yearly epidemics with the ever-present threat of the virus becoming the next pandemic. Due to increasing levels of resistance, several of our previously used antivirals have been rendered useless. There is a strong need for new antivirals that are less likely to be susceptible to mutations. One strategy to achieve this goal is structure-based drug development. By understanding the minute details of protein structure, we can develop antivirals that target the most conserved, crucial regions to yield the highest chances of long-lasting success. One promising IAV target is the virulence protein non-structural protein 1 (NS1). NS1 contributes to pathogenicity through interactions with numerous host proteins, and many of the resulting complexes have been shown to be crucial for virulence. In this review, we cover the NS1-host protein complexes that have been structurally characterized to date. By bringing these structures together in one place, we aim to highlight the strength of this field for drug discovery along with the gaps that remain to be filled.
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Wong, Marcus P., Evan YW Juan, Sophie F. Blanc, Scott B. Biering, Phoebe Wang, Robert Beatty, and Eva Harris. "Investigating the role of inflammasome activation by dengue virus non-structural protein 1 during dengue infection." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 126.06. http://dx.doi.org/10.4049/jimmunol.208.supp.126.06.
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Abstract Dengue virus (DENV), consisting of serotypes 1–4, is the most medically important flavivirus, causing an estimated 50–100 million dengue cases globally every year. Most symptomatic DENV infections present as an acute febrile illness; however, severe complications include vascular leakage leading to hemorrhage and hypovolemic shock. DENV non-structural protein 1 (NS1) is secreted from infected cells and has been implicated as a major driver of dengue pathogenesis, activating immune cells and acting directly on endothelial barriers, causing them to become pathologically hyperpermeable. While recent work has delved into the mechanisms behind the endothelial cell-intrinsic pathway of DENV NS1-induced vascular leak, much less is known about how DENV NS1 interacts with immune cells and what role this activation plays in DENV infection. We have discovered that DENV NS1 can trigger activation of the inflammasome, a family of cytosolic innate immune sensors that react to danger-associated molecular patterns. DENV NS1 induces the release of the pro-inflammatory cytokine IL-1β in human and murine monocytes in a caspase-1 dependent manner that is independent of NLRP3. Additionally, we found that caspase-1-deficient, but not NLRP3-deficient, mice are more susceptible to infection in a murine model of DENV infection. These results indicate that the inflammasome acts as a sensor of the DENV viral toxin NS1 and plays a protective role during DENV infections This work was supported by NIAID/NIH grant R01 AI24493 (E.H.)
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Casseb, Samir Mansour Moraes, Karla Fabiane Lopes de Melo, Carlos Alberto Marques de Carvalho, Carolina Ramos dos Santos, Edna Cristina Santos Franco, and Pedro Fernando da Costa Vasconcelos. "Experimental Dengue Virus Type 4 Infection Increases the Expression of MicroRNAs-15/16, Triggering a Caspase-Induced Apoptosis Pathway." Current Issues in Molecular Biology 45, no. 6 (May 26, 2023): 4589–99. http://dx.doi.org/10.3390/cimb45060291.
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The World Health Organization has estimated the annual occurrence of approximately 392 million dengue virus (DENV) infections in more than 100 countries where the virus is endemic, which represents a serious threat to humanity. DENV is a serologic group with four distinct serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) belonging to the genus Flavivirus, in the family Flaviviridae. Dengue is the most widespread mosquito-borne disease in the world. The ~10.7 kb DENV genome encodes three structural proteins (capsid (C), pre-membrane (prM), and envelope (E)) and seven non-structural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The NS1 protein is a membrane-associated dimer and a secreted, lipid-associated hexamer. Dimeric NS1 is found on membranes both in cellular compartments and cell surfaces. Secreted NS1 (sNS1) is often present in patient serum at very high levels, which correlates with severe dengue symptoms. This study was conducted to discover how the NS1 protein, microRNAs-15/16 (miRNAs-15/16), and apoptosis are related during DENV-4 infection in human liver cell lines. Huh 7.5 and HepG2 cells were infected with DENV-4, and miRNAs-15/16, viral load, NS1 protein, and caspases-3/7 were quantified after different durations of infection. This study demonstrated that miRNAs-15/16 were overexpressed during the infection of HepG2 and Huh 7.5 cells with DENV-4 and had a relationship with NS1 protein expression, viral load, and the activity of caspases-3/7, thus making these miRNAs potential injury markers during DENV infection in human hepatocytes.
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Hauswirth, Patrick, Philipp Graber, Katarzyna Buczak, Riccardo Vincenzo Mancuso, Susanne Heidi Schenk, Jürg P. F. Nüesch, and Jörg Huwyler. "Design and Characterization of Mutated Variants of the Oncotoxic Parvoviral Protein NS1." Viruses 15, no. 1 (January 11, 2023): 209. http://dx.doi.org/10.3390/v15010209.
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Oncotoxic proteins such as the non-structural protein 1 (NS1), a constituent of the rodent parvovirus H1 (H1-PV), offer a novel approach for treatment of tumors that are refractory to other treatments. In the present study, mutated NS1 variants were designed and tested with respect to their oncotoxic potential in human hepatocellular carcinoma cell lines. We introduced single point mutations of previously described important residues of the wild-type NS1 protein and a deletion of 114 base pairs localized within the N-terminal domain of NS1. Cell-viability screening with HepG2 and Hep3B hepatocarcinoma cells transfected with the constructed NS1-mutants led to identification of the single-amino acid NS1-mutant NS1-T585E, which led to a 30% decrease in cell viability as compared to NS1 wildtype. Using proteomics analysis, we could identify new interaction partners and signaling pathways of NS1. We could thus identify new oncotoxic NS1 variants and gain insight into the modes of action of NS1, which is exclusively toxic to human cancer cells. Our in-vitro studies provide mechanistic explanations for the observed oncolytic effects. Expression of NS1 variants had no effect on cell viability in NS1 unresponsive control HepG2 cells or primary mouse hepatocytes. The availability of new NS1 variants in combination with a better understanding of their modes of action offers new possibilities for the design of innovative cancer treatment strategies.
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Jiao, Hanwei, Zonglin Zheng, Xuehong Shuai, Li Wu, Jixuan Chen, Yichen Luo, Yu Zhao, Hongjun Wang, and Qingzhou Huang. "MicroRNA expression profiles from HEK293 cells expressing H5N1 avian influenza virus non-structural protein 1." Innate Immunity 25, no. 2 (February 2019): 110–17. http://dx.doi.org/10.1177/1753425919826342.
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H5N1 avian influenza poses a serious threat to the poultry industry and human health. Non-structural protein 1 (NS1) plays an important role in the replication and pathogenesis of avian influenza virus (AIV). However, the function of the NS1 gene is still unclear. In this study, illumina genome analyzer iix screening was used to identify the differentially expressed microRNAs (miRNAs) in HEK293 cells expressing H5N1 AIV NS1. There were 13 differentially expressed miRNAs (hsa-miR-17-5p, hsa-miR-221-3p, hsa-miR-22-3p, hsa-miR-31-5p, hsa-miR-20a-5p, hsa-miR-222-3p, hsa-miR-24-3p, hsa-miR-3613-3p, hsa-miR-3178, hsa-miR-4505, hsa-miR-345-3p, hsa-miR-3648, and hsa-miR-455-3p) ( P < 0.01). The qRT-PCR validation results demonstrated that hsa-miR-221-3p, hsa-miR-22-3p, hsa-miR-20a-5p, and hsa-miR-3613-3p were upregulated, while hsa-miR-3178 and hsa-miR-4505 were down-regulated. The softwares targetscan and miranda were further used to predict their target genes, and the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis results showed that 20 GO terms and 20 KEGG pathways were significantly enriched. Our findings are the first to report expression profiling of miRNA and their functions in H5N1 AIV NS1-expressing HEK293 cells, and pave the way to further elucidating the accurate interaction mechanism between NS1 and virus replication, thus providing brand new insight into the prophylaxis and treatment of H5N1 AIV.
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Muller, David A., Michael J. Landsberg, Cheryl Bletchly, Rosalba Rothnagel, Lynne Waddington, Ben Hankamer, and Paul R. Young. "Structure of the dengue virus glycoprotein non-structural protein 1 by electron microscopy and single-particle analysis." Journal of General Virology 93, no. 4 (April 1, 2012): 771–79. http://dx.doi.org/10.1099/vir.0.039321-0.
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The flavivirus non-structural protein 1 (NS1) is a glycoprotein that is secreted as a soluble hexameric complex during the course of natural infection. Growing evidence indicates that this secreted form of NS1 (sNS1) plays a significant role in immune evasion and modulation during infection. Attempts to determine the crystal structure of NS1 have been unsuccessful to date and relatively little is known about the macromolecular organization of the sNS1 hexamer. Here, we have applied single-particle analysis to images of baculovirus-derived recombinant dengue 2 virus NS1 obtained by electron microscopy to determine its 3D structure to a resolution of 23 Å. This structure reveals a barrel-like organization of the three dimeric units that comprise the hexamer and provides further insights into the overall organization of oligomeric sNS1.
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Wong, Marcus P., Evan Y. W. Juan, Felix Pahmeier, Sai S. Chelluri, Phoebe Wang, Bryan Castillo-Rojas, Sophie F. Blanc, Scott B. Biering, Russell E. Vance, and Eva Harris. "The inflammasome pathway is activated by dengue virus non-structural protein 1 and is protective during dengue virus infection." PLOS Pathogens 20, no. 4 (April 25, 2024): e1012167. http://dx.doi.org/10.1371/journal.ppat.1012167.
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Dengue virus (DENV) is a medically important flavivirus causing an estimated 50–100 million dengue cases annually, some of whom progress to severe disease. DENV non-structural protein 1 (NS1) is secreted from infected cells and has been implicated as a major driver of dengue pathogenesis by inducing endothelial barrier dysfunction. However, less is known about how DENV NS1 interacts with immune cells and what role these interactions play. Here we report that DENV NS1 can trigger activation of inflammasomes, a family of cytosolic innate immune sensors that respond to infectious and noxious stimuli, in mouse and human macrophages. DENV NS1 induces the release of IL-1β in a caspase-1 dependent manner. Additionally, we find that DENV NS1-induced inflammasome activation is independent of the NLRP3, Pyrin, and AIM2 inflammasome pathways, but requires CD14. Intriguingly, DENV NS1-induced inflammasome activation does not induce pyroptosis and rapid cell death; instead, macrophages maintain cellular viability while releasing IL-1β. Lastly, we show that caspase-1/11-deficient, but not NLRP3-deficient, mice are more susceptible to lethal DENV infection. Together, these results indicate that the inflammasome pathway acts as a sensor of DENV NS1 and plays a protective role during infection.
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Munir, Muhammad, Siamak Zohari, Giorgi Metreveli, Claudia Baule, Sándor Belák, and Mikael Berg. "Alleles A and B of non-structural protein 1 of avian influenza A viruses differentially inhibit beta interferon production in human and mink lung cells." Journal of General Virology 92, no. 9 (September 1, 2011): 2111–21. http://dx.doi.org/10.1099/vir.0.031716-0.
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Non-structural protein 1 (NS1) counteracts the production of host type I interferons (IFN-α/β) for the efficient replication and pathogenicity of influenza A viruses. Here, we reveal another dimension of the NS1 protein of avian influenza A viruses in suppressing IFN-β production in cultured cell lines. We found that allele A NS1 proteins of H6N8 and H4N6 have a strong capacity to inhibit the activation of IFN-β production, compared with allele B from corresponding subtypes, as measured by IFN stimulatory response element (ISRE) promoter activation, IFN-β mRNA transcription and IFN-β protein expression. Furthermore, the ability to suppress IFN-β promoter activation was mapped to the C-terminal effector domain (ED), while the RNA-binding domain (RBD) alone was unable to suppress IFN-β promoter activation. Chimeric studies indicated that when the RBD of allele A was fused to the ED of allele B, it was a strong inhibitor of IFN-β promoter activity. This shows that well-matched ED and RBD are crucial for the function of the NS1 protein and that the RBD could be one possible cause for this differential IFN-β inhibition. Notably, mutagenesis studies indicated that the F103Y and Y103F substitutions in alleles A and B, respectively, do not influence the ISRE promoter activation. Apart from dsRNA signalling, differences were observed in the expression pattern of NS1 in transfected human and mink lung cells. This study therefore expands the versatile nature of the NS1 protein in inhibiting IFN responses at multiple levels, by demonstrating for the first time that it occurs in a manner dependent on allele type.
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Kraivong, Romchat, Somchoke Traewachiwiphak, Napon Nilchan, Nattaya Tangthawornchaikul, Nuntaya Pornmun, Ranyikar Poraha, Kanokwan Sriruksa, et al. "Cross-reactive antibodies targeting surface-exposed non-structural protein 1 (NS1) of dengue virus-infected cells recognize epitopes on the spaghetti loop of the β-ladder domain." PLOS ONE 17, no. 5 (May 26, 2022): e0266136. http://dx.doi.org/10.1371/journal.pone.0266136.
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Non-structural protein 1 (NS1) is a glycoprotein component of dengue virus (DENV) that is essential for viral replication, infection and immune evasion. Immunization with NS1 has been shown to elicit antibody-mediated immune responses which protect mice against DENV infections. Here, we obtained peripheral blood mononuclear cells from human subjects with secondary dengue infections, which were used to construct a dengue immune phage library displaying single-chain variable fragments. Phage selective for DENV NS1 were obtained by biopanning. Twenty-one monoclonal antibodies (mAbs) against DENV NS1 were generated from the selected phage and characterized in detail. We found most anti-NS1 mAbs used IGHV1 heavy chain antibody genes. The mAbs were classified into strongly and weakly-reactive groups based on their binding to NS1 expressed in dengue virus 2 (DENV2)-infected cells. Antibody binding experiments with recombinant NS1 proteins revealed that the mAbs recognize conformational epitopes on the β-ladder domain (amino acid residues 178–273) of DENV NS1. Epitope mapping studies on alanine-substituted NS1 proteins identified distinct but overlapping epitopes. Protruding amino acids distributed around the spaghetti loop are required for the binding of the strongly-reactive mAbs, whereas the recognition residues of the weakly-reactive mAbs are likely to be located in inaccessible sites facing toward the cell membrane. This information could guide the design of an NS1 epitope-based vaccine that targets cross-reactive conserved epitopes on cell surface-associated DENV NS1.
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Noisakran, Sansanee, Thanyaporn Dechtawewat, Panisadee Avirutnan, Taroh Kinoshita, Uamporn Siripanyaphinyo, Chunya Puttikhunt, Watchara Kasinrerk, Prida Malasit, and Nopporn Sittisombut. "Association of dengue virus NS1 protein with lipid rafts." Journal of General Virology 89, no. 10 (October 1, 2008): 2492–500. http://dx.doi.org/10.1099/vir.0.83620-0.
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During the replication of dengue virus, a viral non-structural glycoprotein, NS1, associates with the membrane on the cell surface and in the RNA replication complex. NS1 lacks a transmembrane domain, and the mechanism by which it associates with the membrane remains unclear. This study aimed to investigate whether membrane-bound NS1 is present in lipid rafts in dengue virus-infected cells. Double immunofluorescence staining of infected HEK-293T cells revealed that NS1 localized with raft-associated molecules, ganglioside GM1 and CD55, on the cell surface. In a flotation gradient centrifugation assay, a small proportion of NS1 in Triton X-100 cell lysate consistently co-fractionated with raft markers. Association of NS1 with lipid rafts was detected for all four dengue serotypes, as well as for Japanese encephalitis virus. Analysis of recombinant NS1 forms showed that glycosylated NS1 dimers stably expressed in HEK-293T cells without an additional C-terminal sequence, or with a heterologous transmembrane domain, failed to associate with lipid rafts. In contrast, glycosylphosphatidylinositol-linked recombinant NS1 exhibited a predilection for lipid rafts. These results indicate an association of a minor subpopulation of NS1 with lipid rafts during dengue virus infection and suggest that modification of NS1, possibly lipidation, is required for raft association.
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Salat, Jiri, Petra Strakova, and Daniel Ruzek. "Dynamics of Whole Virus and Non-Structural Protein 1 (NS1) IgG Response in Mice Immunized with Two Commercial Tick-Borne Encephalitis Vaccines." Vaccines 10, no. 7 (June 23, 2022): 1001. http://dx.doi.org/10.3390/vaccines10071001.
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The presence of a non-structural protein 1 (NS1) in tick-borne encephalitis (TBE) vaccines and the possible induction of an NS1-specific immune response in vaccinated individuals remains a somewhat controversial topic. Previously, we detected the presence of NS1 in the Encepur TBE vaccine by mass spectrometry and found the induction of NS1-specific IgG antibodies in mice vaccinated with the FSME-Immun TBE vaccine. Here, in this follow-up study, we examined the dynamics and extent of the NS1-specific IgG response in mice vaccinated with these two vaccines in more detail and compared it with the IgG response to the whole virus (WV). Mice were vaccinated at two-week intervals with a total of six doses of each vaccine, and levels of IgG antibodies to TBE virus WV and NS1 were measured by ELISA after each dose. Both vaccines elicited a robust anti-WV IgG response after two doses. The Encepur vaccine did not elicit NS1-specific IgG even after all six doses. In contrast, the FSME-Immun vaccine triggered the production of NS1-specific IgG after four doses. The results indicate that FSME-Immun is the only vaccine that elicits an NS1-specific antibody response in mice. However, compared to WV-specific IgG, the NS1-specific response is weaker, and a higher number of doses is required to induce detectable levels of NS1-specific IgG antibodies.
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Wacquiez, Alan, Franck Coste, Emmanuel Kut, Virginie Gaudon, Sascha Trapp, Bertrand Castaing, and Daniel Marc. "Structure and Sequence Determinants Governing the Interactions of RNAs with Influenza A Virus Non-Structural Protein NS1." Viruses 12, no. 9 (August 27, 2020): 947. http://dx.doi.org/10.3390/v12090947.
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The non-structural protein NS1 of influenza A viruses is an RNA-binding protein of which its activities in the infected cell contribute to the success of the viral cycle, notably through interferon antagonism. We have previously shown that NS1 strongly binds RNA aptamers harbouring virus-specific sequence motifs (Marc et al., Nucleic Acids Res. 41, 434–449). Here, we started out investigating the putative role of one particular virus-specific motif through the phenotypic characterization of mutant viruses that were genetically engineered from the parental strain WSN. Unexpectedly, our data did not evidence biological importance of the putative binding of NS1 to this specific motif (UGAUUGAAG) in the 3′-untranslated region of its own mRNA. Next, we sought to identify specificity determinants in the NS1-RNA interaction through interaction assays in vitro with several RNA ligands and through solving by X-ray diffraction the 3D structure of several complexes associating NS1′s RBD with RNAs of various affinities. Our data show that the RBD binds the GUAAC motif within double-stranded RNA helices with an apparent specificity that may rely on the sequence-encoded ability of the RNA to bend its axis. On the other hand, we showed that the RBD binds to the virus-specific AGCAAAAG motif when it is exposed in the apical loop of a high-affinity RNA aptamer, probably through a distinct mode of interaction that still requires structural characterization. Our data are consistent with more than one mode of interaction of NS1′s RBD with RNAs, recognizing both structure and sequence determinants.
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Tan, Min Jie Alvin, Nancy G. Brown, Kitti Wing Ki Chan, Jocelyn Y. Jin, Sean Yao Zu Kong, and Subhash G. Vasudevan. "Mutations in the cytoplasmic domain of dengue virus NS4A affect virus fitness and interactions with other non-structural proteins." Journal of General Virology 101, no. 9 (September 1, 2020): 941–53. http://dx.doi.org/10.1099/jgv.0.001462.
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The dengue virus (DENV) replication complex is made up of its non-structural (NS) proteins and yet-to-be identified host proteins, but the molecular interactions between these proteins are not fully elucidated. In this work, we sought to uncover the interactions between DENV NS1 and its fellow NS proteins using a yeast two-hybrid (Y2H) approach, and found that domain II of NS1 binds to an N-terminal cytoplasmic fragment of NS4A. Mutations in amino acid residues 41 and 43 in this cytoplasmic region of NS4A disrupted the interaction between NS1 and the NS4A-2K-4B precursor protein. When the NS4A Y41F mutation was introduced into the context of the virus via a DENV2 infectious clone, this mutant virus exhibited impaired viral fitness and decreased infectious virus production. The NS4A Y41F mutant virus triggered a significantly muted transcriptional activation of interferon-stimulated genes compared to wild-type virus that is independent of NS4A’s ability to antagonize type I interferon signalling. Taken together, we have identified a link between DENV NS1 and the cytoplasmic domain in NS4A that is important for its cellular and viral functions.
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Alvisi, Gualtiero, Elisabetta Manaresi, Silvia Pavan, David A. Jans, Kylie M. Wagstaff, and Giorgio Gallinella. "Avermectins Inhibit Replication of Parvovirus B19 by Disrupting the Interaction Between Importin α and Non-Structural Protein 1." Viruses 17, no. 2 (February 3, 2025): 220. https://doi.org/10.3390/v17020220.
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Human parvovirus B19 (B19V) is a major human pathogen in which the ssDNA genome is replicated within the nucleus of infected human erythroid progenitor cells (EPCs) through a process involving both cellular and viral proteins, including the non-structural protein (NS)1. We previously characterized the interaction between NS1 classical nuclear localization signal (cNLS: GACHAKKPRIT-182) and host cell importin (IMP)α and proposed it as a potential target for antiviral drug development. Here, we further extend on such findings. First, we demonstrate that NS1 nuclear localization is required for viral production since introducing the K177T substitution in a cloned, infectious viral genome resulted in a non-viable virus. Secondly, we demonstrate that the antiparasitic drug ivermectin (IVM), known to inhibit the IMPα/β dependent nuclear import pathway, could impair the NS1-NLS:IMPα interaction and suppress viral replication in UT7/EpoS1 cells in a dose-dependent manner. We also show that a panel of structurally related avermectins (AVMs) can dissociate the NS1-NLS:IMPα complex with half-maximal inhibitory concentrations in the nanomolar range. Among them, Eprinomectin emerged as the most selective inhibitor of B19V replication, with a selectivity index of c. 5.0. However, when tested in EPCs generated from peripheral blood mononuclear cells, which constitute a cellular population close to the natural target cells in bone marrow, the inhibitory effect of IVM and Eprinomectin was demonstrated to a lesser extent, and both compounds exhibited high toxicity, thus highlighting the need for more specific inhibitors of the NS1-NLS:IMPα interaction.
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Meunier, Isabelle, and Veronika von Messling. "NS1-mediated delay of type I interferon induction contributes to influenza A virulence in ferrets." Journal of General Virology 92, no. 7 (July 1, 2011): 1635–44. http://dx.doi.org/10.1099/vir.0.032193-0.
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Interference of the influenza A virus non-structural protein NS1 with type I interferon (IFN) signalling has been characterized extensively in vitro. To assess the contribution of NS1 to the virulence of a specific strain, we generated recombinant USSR/90/77 viruses bearing the NS1 proteins of the attenuated strain PR/8/34 or the highly pathogenic strain 1918 ‘Spanish flu’, all belonging to the H1N1 subtype. In vitro, the extent of interference with type I IFN production exerted by the different NS1 proteins correlated with the reported virulence of the respective strain. Infection of ferrets with the recombinant viruses revealed that the presence of the 1918 NS1 resulted in a slightly more severe disease with generally higher clinical scores and increased lung pathology. Analysis of mRNA from nasal wash cells revealed that viruses carrying the 1918 and, to a lesser extent, USSR/90/77 NS1 proteins caused a delay in upregulation of type I IFNs compared with the NS1 PR/8/34-expressing virus, demonstrating the importance of NS1 for early host-response control and virulence.
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Lamotte, Laurie-Anne, and Lionel Tafforeau. "How Influenza A Virus NS1 Deals with the Ubiquitin System to Evade Innate Immunity." Viruses 13, no. 11 (November 19, 2021): 2309. http://dx.doi.org/10.3390/v13112309.
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Ubiquitination is a post-translational modification regulating critical cellular processes such as protein degradation, trafficking and signaling pathways, including activation of the innate immune response. Therefore, viruses, and particularly influenza A virus (IAV), have evolved different mechanisms to counteract this system to perform proper infection. Among IAV proteins, the non-structural protein NS1 is shown to be one of the main virulence factors involved in these viral hijackings. NS1 is notably able to inhibit the host’s antiviral response through the perturbation of ubiquitination in different ways, as discussed in this review.
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Xisto, Mariana Fonseca, John Willians Oliveira Prates, Ingrid Marques Dias, Roberto Sousa Dias, Cynthia Canedo da Silva, and Sérgio Oliveira de Paula. "NS1 Recombinant Proteins Are Efficiently Produced in Pichia pastoris and Have Great Potential for Use in Diagnostic Kits for Dengue Virus Infections." Diagnostics 10, no. 6 (June 6, 2020): 379. http://dx.doi.org/10.3390/diagnostics10060379.
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Dengue is one of the major diseases causing global public health concerns. Despite technological advances in vaccine production against all its serotypes, it is estimated that the dengue virus is responsible for approximately 390 million infections per year. Laboratory diagnosis has been the key point for the correct treatment and prevention of this disease. Currently, the limiting factor in the manufacture of dengue diagnostic kits is the large-scale production of the non-structural 1 (NS1) antigen used in the capture of the antibody present in the infected patients’ serum. In this work, we demonstrate the production of the non-structural 1 protein of dengue virus (DENV) serotypes 1–4 (NS1-DENV1, NS1-DENV2, NS1-DENV3, and NS1-DENV4) in the methylotrophic yeast Pichia pastoris KM71H. Secreted recombinant protein was purified by affinity chromatography and characterized by SDS-PAGE and ELISA. The objectives of this study were achieved, and the results showed that P. pastoris is a good heterologous host and worked well in the production of NS1DENV 1–4 recombinant proteins. Easy to grow and quick to obtain, this yeast secreted ready-to-use proteins, with a final yield estimated at 2.8–4.6 milligrams per liter of culture. We reached 85–91% sensitivity and 91–93% specificity using IgM as a target, and for anti-dengue IgG, 83–87% sensitivity and 81–93% specificity were achieved. In this work, we conclude that the NS1 recombinant proteins are efficiently produced in P. pastoris and have great potential for use in diagnostic kits for dengue virus infections. The transformed yeast obtained can be used for production in industrial-scale bioreactors.
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Li, Guohui, Chen Sun, Junhong Zhang, Yuanqing He, Huiqing Chen, Jie Kong, Guoping Huang, Keping Chen, and Qin Yao. "Characterization of Bombyx mori parvo-like virus non-structural protein NS1." Virus Genes 39, no. 3 (October 9, 2009): 396–402. http://dx.doi.org/10.1007/s11262-009-0402-x.
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Lim, Pei-Yin, Appanna Ramapraba, Thomas Loy, Angeline Rouers, Tun-Linn Thein, Yee-Sin Leo, Dennis R. Burton, Katja Fink, and Cheng-I. Wang. "A nonstructural protein 1 capture enzyme-linked immunosorbent assay specific for dengue viruses." PLOS ONE 18, no. 5 (May 18, 2023): e0285878. http://dx.doi.org/10.1371/journal.pone.0285878.
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Dengue non-structural protein (NS1) is an important diagnostic marker during the acute phase of infection. Because NS1 is partially conserved across the flaviviruses, a highly specific DENV NS-1 diagnostic test is needed to differentiate dengue infection from Zika virus (ZIKV) infection. In this study, we characterized three newly isolated antibodies against NS1 (A2, D6 and D8) from a dengue-infected patient and a previously published human anti-NS1 antibody (Den3). All four antibodies recognized multimeric forms of NS1 from different serotypes. A2 bound to NS1 from DENV-1, -2, and -3, D6 bound to NS1 from DENV-1, -2, and -4, and D8 and Den3 interacted with NS1 from all four dengue serotypes. Using a competition ELISA, we found that A2 and D6 bound to overlapping epitopes on NS1 whereas D8 recognized an epitope distinct from A2 and D6. In addition, we developed a capture ELISA that specifically detected NS1 from dengue viruses, but not ZIKV, using Den3 as the capture antibody and D8 as the detecting antibody. This assay detected NS1 from all the tested dengue virus strains and dengue-infected patients. In conclusion, we established a dengue-specific capture ELISA using human antibodies against NS1. This assay has the potential to be developed as a point-of-care diagnostic tool.
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Rahim, Md Niaz, Mohammed Selman, Patricia J. Sauder, Nicole E. Forbes, William Stecho, Wanhong Xu, Mark Lebar, Earl G. Brown, and Kevin M. Coombs. "Generation and characterization of a new panel of broadly reactive anti-NS1 mAbs for detection of influenza A virus." Journal of General Virology 94, no. 3 (March 1, 2013): 593–605. http://dx.doi.org/10.1099/vir.0.046649-0.
Full textAbstract:
Influenza A virus (IAV) non-structural protein 1 (NS1) has multiple functions, is essential for virus replication and may be a good target for IAV diagnosis. To generate broadly cross-reactive NS1-specific mAbs, mice were immunized with A/Hong Kong/1/1968 (H3N2) 6×His-tagged NS1 and hybridomas were screened with glutathione S-transferase-conjugated NS1 of A/Puerto Rico/8/1934 (H1N1). mAbs were isotyped and numerous IgG-type clones were characterized further. Most clones specifically recognized NS1 from various H1N1 and H3N2 IAV types by both immunoblot and immunofluorescence microscopy in mouse M1, canine Madin–Darby canine kidney and human A549 cells. mAb epitopes were mapped by overlapping peptides and selective reactivity to the newly described viral NS3 protein. These mAbs detected NS1 in both the cytoplasm and nucleus by immunostaining, and some detected NS1 as early as 5 h post-infection, suggesting their potential diagnostic use for tracking productive IAV replication and characterizing NS1 structure and function. It was also demonstrated that the newly identified NS3 protein is localized in the cytoplasm to high levels.
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Das, Ujjal, Mamta Chawla-Sarkar, Swati Roy Gangopadhyay, Sanjit Dey, and Rakhi Dey Sharma. "Role of Influenza A virus protein NS1 in regulating host nuclear body ND10 complex formation and its involvement in establishment of viral pathogenesis." PLOS ONE 19, no. 1 (January 2, 2024): e0295522. http://dx.doi.org/10.1371/journal.pone.0295522.
Full textAbstract:
Influenza viral infection is a seasonal infection which causes widespread acute respiratory issues among humans globally. This virus changes its surface receptor composition to escape the recognition process by the host’s immune cells. Therefore, the present study focussed to identify some other important viral proteins which have a significant role in establishment of infection and having apparent conserved structural composition. This could facilitate the permanent vaccine development process or help in designing a drug against IAV (influenza A virus) infection which will eliminate the seasonal flu shot vaccination process. The NS1 (Non-structural protein 1) protein of IAV maintains a conserved structural motif. Earlier studies have shown its significant role in infection establishment. However, the mechanism by which viruses escape the host’s ND10 antiviral action remains elusive. The present study clearly showed that IAV infection and NS1 transfection in A549 cells degraded the main component of the ND10 anti-viral complex, PML and therefore, inhibited the formation of Daxx-sp100-p53-PML complex (ND10) at the mid phase of infection/transfection. PML degradation activated the stress axis which increased cellular ROS (reactive oxygen species) levels as well as mitochondrial dysfunction. Additionally, IAV/NS1 increased cellular stress and p53 accumulation at the late phase of infection. These collectively activated apoptotic pathway in the host cells. Along with the inactivation of several interferon proteins, IAV was found to decrease p-IKKε. A549 cells transfected with pcDNA3.1-NS1 showed a similar effect in the interferon axis and IKKε. Moreover, NS1 induced the disintegration of the host’s ND10 complex through the changes in the SUMOylation pattern of the PML nuclear body. These findings suggest the possible mechanism of how NS1 helps IAV to establish infection in the host cells. However, it demands further detailed study before targeting NS1 to develop permanent vaccines or novel drugs against IAV in future.
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Ogire, Eva, Chaker El-Kalamouni, Philippe Desprès, and Marjolaine Roche. "Stability of Dengue 2 Nonstructural Glycoprotein 1 (NS1) Is Affected by the Nature of Basic Residue at Position NS1-324." Current Issues in Molecular Biology 45, no. 2 (February 14, 2023): 1644–54. http://dx.doi.org/10.3390/cimb45020106.
Full textAbstract:
Dengue is the most prevalent mosquito-borne viral disease. It is caused by the infection of any of the four dengue virus (DENV) serotypes DENV-1 to DENV-4. The DENV non-structural glycoprotein 1 (NS1) plays an important role in virus replication and the immunopathogenesis of virus infection. The NS1 protein has been identified as both a cell-associated homodimer and a soluble secreted lipoprotein nanoparticle. The nature of the residues at positions NS1-272 and NS1-324 in the β-ladder domain may have an effect on the biological behaviors of DENV-2 NS1 protein in human hepatoma Huh7 cells. The stability of the NS1 protein from the Reunion 2018 DENV-2 strain was affected by the presence of lysine residues at positions 272 and 324. In the present study, we evaluated the impact of mutations into lysine at positions 272 and 324 on recombinant NS1 protein from the DES-14 DENV-2 strain bearing arginine residue on these two positions. The DES-14 NS1 protein mutant bearing a lysine at position 324 was deficient in protein stability and secretion compared to wild-type protein. The defect in the DES-14 NS1 protein mutant was associated to oxidative stress and pro-inflammatory cytokine activation in Huh7 cells. The ubiquitin-proteasome proteolytic pathway might play a key role in the stability of DENV-2 protein bearing a lysine residue at position 324.
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Sun, En-Cheng, Jing Zhao, Ni-Hong Liu, Tao Yang, Jian-Nan Ma, Hong-Wei Geng, Ling-Feng Wang, et al. "Comprehensive mapping of West Nile virus (WNV)- and Japanese encephalitis virus serocomplex-specific linear B-cell epitopes from WNV non-structural protein 1." Journal of General Virology 93, no. 1 (January 1, 2012): 50–60. http://dx.doi.org/10.1099/vir.0.034900-0.
Full textAbstract:
West Nile virus (WNV) non-structural protein 1 (NS1) elicits protective immune responses during infection of animals. WNV NS1-specific antibody responses can provide the basis for serological diagnostic reagents, so the antigenic sites in NS1 that are targeted by host immune responses need to be identified and the conservation of these sites among the Japanese encephalitis virus (JEV) serocomplex members also needs to be defined. The present study describes the mapping of linear B-cell epitopes in WNV NS1. We screened eight NS1-specific mAbs and antisera (polyclonal antibodies; pAbs) from mice immunized with recombinant NS1 for reactivity against 35 partially overlapping peptides covering the entire WNV NS1. The screen using mAbs identified four WNV-specific (including Kunjin virus) epitopes, located at aa 21–36, 101–116, 191–206 and 261–276 in WNV NS1. However, using pAbs, only three WNV-specific epitopes were identified, located at positions 101–116, 191–206 and 231–246. Two of these epitopes (aa 21–36 and 261–276) had different reactivity with mAbs and pAbs. The knowledge and reagents generated in this study have potential applications in differential diagnostics and epitope-based marker vaccine development for WNV and viruses of the JEV serocomplex.
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Kochs, Georg, Iris Koerner, Lena Thiel, Sonja Kothlow, Bernd Kaspers, Nicolas Ruggli, Artur Summerfield, Jovan Pavlovic, Jürgen Stech, and Peter Staeheli. "Properties of H7N7 influenza A virus strain SC35M lacking interferon antagonist NS1 in mice and chickens." Journal of General Virology 88, no. 5 (May 1, 2007): 1403–9. http://dx.doi.org/10.1099/vir.0.82764-0.
Full textAbstract:
Non-structural protein NS1 of influenza A virus counteracts the host immune response by blocking the synthesis of type I interferon (IFN). As deletion of the complete NS1 gene has to date been reported only in the human H1N1 strain A/PR/8/34, it remained unclear whether NS1 is a non-essential virulence factor in other influenza A virus strains as well. In this report, the properties of NS1-deficient mutants derived from strain SC35M (H7N7) are described. A mutant of SC35M that completely lacks the NS1 gene was an excellent inducer of IFN in mammalian and avian cells in culture and, consequently, was able to multiply efficiently only in cell lines with defects in the type I IFN system. Virus mutants carrying C-terminally truncated versions of NS1 were less powerful inducers of IFN and were attenuated less strongly in human A549 cells. Although attenuated in wild-type mice, these mutants remained highly pathogenic for mice lacking the IFN-regulated antiviral factor Mx1. In contrast, the NS1-deficient SC35M mutant was completely non-pathogenic for wild-type mice, but remained pathogenic for mice lacking Mx1 and double-stranded RNA-activated protein kinase (PKR). Wild-type SC35M, but not the NS1-deficient mutant virus, was able to replicate in the upper respiratory tract of birds, but neither virus induced severe disease in adult chickens. Altogether, this study supports the view that NS1 represents a non-essential virulence factor of different influenza A viruses.
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Tessmer, Claudia, Claudia Plotzky, Jana Fees, Hendrik Welsch, Rebecca Eudenbach, Martin Faber, Alicia Simón, et al. "Generation and Validation of Monoclonal Antibodies Suitable for Detecting and Monitoring Parvovirus Infections." Pathogens 11, no. 2 (February 4, 2022): 208. http://dx.doi.org/10.3390/pathogens11020208.
Full textAbstract:
For many applications it is necessary to detect target proteins in living cells. This is particularly the case when monitoring viral infections, in which the presence (or absence) of distinct target polypeptides potentially provides vital information about the pathology caused by the agent. To obtain suitable tools with which to monitor parvoviral infections, we thus generated monoclonal antibodies (mAbs) in order to detect the major non-structural protein NS1 in the intracellular environment and tested them for sensitivity and specificity, as well as for cross-reactivity towards related species. Using different immunogens and screening approaches based on indirect immunofluorescence, we describe here a panel of mAbs suitable for monitoring active infections with various parvovirus species by targeting the major non-structural protein NS1. In addition to mAbs detecting the NS1 of parvovirus H-1 (H-1PV) (belonging to the Rodent protoparvovirus 1 species, which is currently under validation as an anti-cancer agent), we generated tools with which to monitor infections by human cutavirus (CuV) and B19 virus (B19V) (belonging to the Primate protoparvovirus 3 and the Primate erythroparvovirus 1 species, respectively, which were both found to persistently infect human tissues). As well as mAbs able to detect NS1 from a broad range of parvoviruses, we obtained entities specific for either (distinct) members of the Rodent protoparvovirus 1 species, human CuV, or human B19V.
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Rosário-Ferreira, Nícia, António J. Preto, Rita Melo, Irina S. Moreira, and Rui M. M. Brito. "The Central Role of Non-Structural Protein 1 (NS1) in Influenza Biology and Infection." International Journal of Molecular Sciences 21, no. 4 (February 22, 2020): 1511. http://dx.doi.org/10.3390/ijms21041511.
Full textAbstract:
Influenza (flu) is a contagious viral disease, which targets the human respiratory tract and spreads throughout the world each year. Every year, influenza infects around 10% of the world population and between 290,000 and 650,000 people die from it according to the World Health Organization (WHO). Influenza viruses belong to the Orthomyxoviridae family and have a negative sense eight-segment single-stranded RNA genome that encodes 11 different proteins. The only control over influenza seasonal epidemic outbreaks around the world are vaccines, annually updated according to viral strains in circulation, but, because of high rates of mutation and recurrent genetic assortment, new viral strains of influenza are constantly emerging, increasing the likelihood of pandemics. Vaccination effectiveness is limited, calling for new preventive and therapeutic approaches and a better understanding of the virus–host interactions. In particular, grasping the role of influenza non-structural protein 1 (NS1) and related known interactions in the host cell is pivotal to better understand the mechanisms of virus infection and replication, and thus propose more effective antiviral approaches. In this review, we assess the structure of NS1, its dynamics, and multiple functions and interactions, to highlight the central role of this protein in viral biology and its potential use as an effective therapeutic target to tackle seasonal and pandemic influenza.
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Patel, Sameera, Alessandro Sinigaglia, Luisa Barzon, Matteo Fassan, Florian Sparber, Salome LeibundGut-Landmann, and Mathias Ackermann. "Role of NS1 and TLR3 in Pathogenesis and Immunity of WNV." Viruses 11, no. 7 (July 3, 2019): 603. http://dx.doi.org/10.3390/v11070603.
Full textAbstract:
West Nile Virus (WNV) is a mosquito-transmitted flavivirus which causes encephalitis especially in elderly and immunocompromised individuals. Previous studies have suggested the protective role of the Toll-like receptor 3 (TLR3) pathway against WNV entry into the brain, while the WNV non-structural protein 1 (NS1) interferes with the TLR3 signaling pathway, besides being a component of viral genome replication machinery. In this study, we investigated whether immunization with NS1 could protect against WNV neuroinvasion in the context of TLR3 deficiency. We immunized mice with either an intact or deleted TLR3 system (TLR3KO) with WNV envelope glycoprotein (gE) protein, NS1, or a combination of gE and NS1. Immunization with gE or gE/NS1, but not with NS1 alone, induced WNV neutralizing antibodies and protected against WNV brain invasion and inflammation. The presence of intact TLR3 signaling had no apparent effect on WNV brain invasion. However, mock-immunized TLR3KO mice had higher inflammatory cell invasion upon WNV brain infection than NS1-immunized TLR3KO mice and wild type mice. Thus, immunization against NS1 may reduce brain inflammation in a context of TLR3 signaling deficiency.
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Marc, Daniel. "Stop-codon variations in non-structural protein NS1 of avian influenza viruses." Virulence 7, no. 5 (April 8, 2016): 498–501. http://dx.doi.org/10.1080/21505594.2016.1175802.
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