Flavivirus NS1 and Its Potential in Vaccine Development.
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ABSTRACT:
SUBMITTER: Carpio KL
PROVIDER: S-EPMC8229460 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Flaviviruses are emerging arthropod-borne viruses representing an immense global health problem. The prominent viruses of this group include dengue virus, yellow fever virus, Japanese encephalitis virus, West Nile virus tick borne encephalitis virus and Zika Virus. These are endemic in many parts of the world. They are responsible for the illness ranging from mild flu like symptoms to severe hemorrhagic, neurologic and cognitive manifestations leading to death. NS1 is a highly conserved non-structural protein among flaviviruses, which exist in diverse forms. The intracellular dimer form of NS1 plays role in genome replication, whereas, the secreted hexamer plays role in immune evasion. The secreted NS1 has been identified as a potential diagnostic marker for early detection of the infections caused by flaviviruses. In addition to the diagnostic marker, the importance of NS1 has been reported in the development of therapeutics. NS1 based subunit vaccines are at various stages of development. The structural details and diverse functions of NS1 have been discussed in detail in this review.
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Project description:The Flavivirus nonstructural protein 1 (NS1) is a conserved, membrane-associated and secreted glycoprotein with replication and immune evasion functions. Secreted NS1 is a hexameric, barrel-shaped lipoprotein that can bind back to the plasma membrane of cells. Antibodies targeting cell surface-associated NS1 can be protective in vivo in a manner dependent on Fc effector functions. We describe here the crystal structure of a C-terminal fragment (residues 172-352) of West Nile (WNV) and Dengue virus NS1 proteins at 1.85 and 2.7 Å resolution, respectively. NS1(172-352) assembles as a unique rod-shaped dimer composed of a 16-stranded ?-platform flanked on one face by protruding connecting loops. We also determined the 3.0 Å resolution structure of WNV NS1(172-352) with the protective 22NS1 antibody Fab, which engages the loop-face of the rod. The head-to-head NS1(172-352) dimer we observe in crystal lattices is supported by multiangle light and small-angle X-ray scattering studies. We used the available cryo-electron microscopy reconstruction to develop a pseudoatomic model of the NS1 hexamer. The model was constructed with the NS1(172-352) dimeric rod aligned with the long axis of the barrel, and with the loop-face oriented away from the core. Difference densities suggest that the N-terminal region of NS1 forms globular lobes that mediate lateral contacts between dimers in the hexamer. Our model also suggests that the N-terminal lobe forms the surface of the central cavity where lipid binding may occur.
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Project description:The flavivirus genus contains several clinically important pathogens that account for tremendous global suffering. Primarily transmitted by mosquitos or ticks, these viruses can cause severe and potentially fatal diseases ranging from hemorrhagic fevers to encephalitis. The extensive global burden is predominantly caused by six flaviviruses: dengue, Zika, West Nile, yellow fever, Japanese encephalitis and tick-borne encephalitis. Several vaccines have been developed, and many more are currently being tested in clinical trials. However, flavivirus vaccine development is still confronted with many shortcomings and challenges. With the use of the existing literature, we have studied these hurdles as well as the signs of progress made in flavivirus vaccinology in the context of future development strategies. Moreover, all current licensed and phase-trial flavivirus vaccines have been gathered and discussed based on their vaccine type. Furthermore, potentially relevant vaccine types without any candidates in clinical testing are explored in this review as well. Over the past decades, several modern vaccine types have expanded the field of vaccinology, potentially providing alternative solutions for flavivirus vaccines. These vaccine types offer different development strategies as opposed to traditional vaccines. The included vaccine types were live-attenuated, inactivated, subunit, VLPs, viral vector-based, epitope-based, DNA and mRNA vaccines. Each vaccine type offers different advantages, some more suitable for flaviviruses than others. Additional studies are needed to overcome the barriers currently faced by flavivirus vaccine development, but many potential solutions are currently being explored.
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Project description:Even in countries that are currently not facing a flavivirus epidemic, the spread of mosquito-borne flaviviruses presents an increasing public threat, owing to climate change, international travel, and other factors. Many of these countries lack the resources (viral strains, clinical specimens, etc.) needed for the research that could help cope with the threat imposed by flaviviruses, and therefore, an alternative approach is needed. Using an in silico approach to global databases, we aimed to design and develop flavivirus NS1 recombinant proteins with due consideration towards antigenic variation. NS1 genes analyzed in this study included a total of 6,823 sequences, from Dengue virus (DENV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Zika virus (ZIKV), and Yellow fever virus (YKV). We extracted and analyzed 316 DENV NS1 sequence types (STs), 59 JEV STs, 75 WNV STs, 30 YFV STs, and 43 ZIKV STs using a simple algorithm based on phylogenetic analysis. STs were reclassified according to the variation of the major epitope by MHC II binding. 78 DENV epitope type (EpT), 29 JEV EpTs, 29 WNV EpTs, 12 YFV EpTs, and 5 ZIKV EpTs were extracted according to their major epitopes. Also, frequency results showed that there were dominant EpTs in all flavivirus. Fifteen STs were selected and purified for the expression of recombinant antigen in Escherichia coli by sodium dodecyl sulfate extraction. Our study details a novel in silico approach for the development of flavivirus diagnostics, including a simple way to screen the important peptide regions.
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Project description:The global spread of Zika virus (ZIKV) and its unexpected association with congenital defects necessitates the rapid development of a safe and effective vaccine. Here we report the development and characterization of a recombinant chimeric ZIKV vaccine candidate (termed ChinZIKV) that expresses the prM-E proteins of ZIKV using the licensed Japanese encephalitis live-attenuated vaccine SA14-14-2 as the genetic backbone. ChinZIKV retains its replication activity and genetic stability in vitro, while exhibiting an attenuation phenotype in multiple animal models. Remarkably, immunization of mice and rhesus macaques with a single dose of ChinZIKV elicits robust and long-lasting immune responses, and confers complete protection against ZIKV challenge. Significantly, female mice immunized with ChinZIKV are protected against placental and fetal damage upon ZIKV challenge during pregnancy. Overall, our study provides an alternative vaccine platform in response to the ZIKV emergency, and the safety, immunogenicity, and protection profiles of ChinZIKV warrant further clinical development.
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Project description:We highlight the various domains of the flavivirus virulence factor NS1 and speculate on potential implications of the NS1 3D structure in understanding its role in flavivirus pathogenesis. Flavivirus non-structural protein 1 (NS1) is a virulence factor with dual functions in genome replication and immune evasion. Crystal structures of NS1, combined with reconstructions from electron microscopy (EM), provide insight into the architecture of dimeric NS1 on cell membranes and the assembly of a secreted hexameric NS1-lipid complex found in patient sera. Three structural domains of NS1 likely have distinct roles in membrane association, replication complex assembly, and immune system avoidance. A conserved hydrophobic inner face is sequestered either on the membrane or in the interior of the secreted hexamer and contains regions implicated in viral replication. The exposed variable outer face is presented to cellular and secreted components of the immune system in infected patients and contains candidate regions for immune system modulation. We anticipate that knowledge of the distinct NS1 domains and assembly will lead to advances in elucidating virus-host interactions mediated through NS1 and in dissecting the role of NS1 in viral genome replication.
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Project description:Medically important flaviviruses cause diverse disease pathologies and collectively are responsible for a major global disease burden. A contributing factor to pathogenesis is secreted flavivirus nonstructural protein 1 (NS1). Despite demonstrated protection by NS1-specific antibodies against lethal flavivirus challenge, the structural and mechanistic basis remains unknown. Here, we present three crystal structures of full-length dengue virus NS1 complexed with a flavivirus-cross-reactive, NS1-specific monoclonal antibody, 2B7, at resolutions between 2.89 and 3.96 angstroms. These structures reveal a protective mechanism by which two domains of NS1 are antagonized simultaneously. The NS1 wing domain mediates cell binding, whereas the β-ladder triggers downstream events, both of which are required for dengue, Zika, and West Nile virus NS1-mediated endothelial dysfunction. These observations provide a mechanistic explanation for 2B7 protection against NS1-induced pathology and demonstrate the potential of one antibody to treat infections by multiple flaviviruses.
| S-EPMC8000976 | biostudies-literature
Project description:Flaviviruses cause systemic or neurotropic-encephalitic pathology in humans. The flavivirus nonstructural protein 1 (NS1) is a secreted glycoprotein involved in viral replication, immune evasion, and vascular leakage during dengue virus infection. However, the contribution of secreted NS1 from related flaviviruses to viral pathogenesis remains unknown. Here, we demonstrate that NS1 from dengue, Zika, West Nile, Japanese encephalitis, and yellow fever viruses selectively binds to and alters permeability of human endothelial cells from lung, dermis, umbilical vein, brain, and liver in vitro and causes tissue-specific vascular leakage in mice, reflecting the pathophysiology of each flavivirus. Mechanistically, each flavivirus NS1 leads to differential disruption of endothelial glycocalyx components, resulting in endothelial hyperpermeability. Our findings reveal the capacity of a secreted viral protein to modulate endothelial barrier function in a tissue-specific manner both in vitro and in vivo, potentially influencing virus dissemination and pathogenesis and providing targets for antiviral therapies and vaccine development.
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Project description:The arbovirus life cycle involves viral transfer between a vertebrate host and an arthropod vector, and acquisition of virus from an infected mammalian host by a vector is an essential step in this process. Here, we report that flavivirus nonstructural protein-1 (NS1), which is abundantly secreted into the serum of an infected host, plays a critical role in flavivirus acquisition by mosquitoes. The presence of dengue virus (DENV) and Japanese encephalitis virus NS1s in the blood of infected interferon-? and ? receptor-deficient mice (AG6) facilitated virus acquisition by their native mosquito vectors because the protein enabled the virus to overcome the immune barrier of the mosquito midgut. Active immunization of AG6 mice with a modified DENV NS1 reduced DENV acquisition by mosquitoes and protected mice against a lethal DENV challenge, suggesting that immunization with NS1 could reduce the number of virus-carrying mosquitoes as well as the incidence of flaviviral diseases. Our study demonstrates that flaviviruses utilize NS1 proteins produced during their vertebrate phases to enhance their acquisition by vectors, which might be a result of flavivirus evolution to adapt to multiple host environments.
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Project description:NS1 is an elusive dengue protein, involved in viral replication, assembly, pathogenesis, and immune evasion. Its levels in blood plasm are positively related to disease severity like thrombocytopenia, hemorrhage, and vascular leakage. Despite its pathogenic roles, NS1 is being used in various vaccine formulations due to its sequence conservancy, ability to produce protective antibodies and low risk for inducing antibody-dependent enhancement. In this study, we have used bioinformatics tools and reported literature to develop an NS1 variant (dNS1). Molecular docking studies were performed to evaluate the receptor-binding ability of the NS1 and dNS1 with TLR4. NS1 and dNS1 (153 to 312 amino acid region) genes were cloned, expressed and protein was purified followed by refolding. Docking studies showed the binding of NS1 and dNS1 with the TLR4 receptor which suggests that N and C-terminal sequences of NS1 are not critical for receptor binding. Antibodies against NS1 and dNS1 were raised in rabbits and binding affinity of anti-dNS1 anti-NS1 sera was evaluated against both NS1 and dNS1. Similar results were observed through western blotting which highlight that N and C-terminal deletion of NS1 does not compromise the immunogenic potential of dNS1 hence, supports its use in future vaccine formulations as a substitute for NS1.
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