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Current Opinion in Structural Biology Apr 2009Several structures of complexes between viral attachment proteins and their cellular receptors have been determined recently, enhancing our understanding of the... (Review)
Review
Several structures of complexes between viral attachment proteins and their cellular receptors have been determined recently, enhancing our understanding of the molecular recognition processes that guide formation of virus-receptor complexes. Moreover, these structures also highlight strategies by which highly similar viral proteins within a single virus family can adapt to engage different receptors. Consequences of such differences are altered tropism and pathogenicity. An improved understanding of the molecular details of this specificity switching in receptor binding will help to establish links between receptor tropism, spread, and disease. Moreover, it also has relevance for the design and use of viruses as gene delivery vehicles with altered properties as well as for the identification of target viral epitopes of new vaccines.
Topics: Adenoviridae; Amino Acid Sequence; Animals; Coxsackie and Adenovirus Receptor-Like Membrane Protein; Epitopes; Gene Transfer Techniques; Humans; Membrane Cofactor Protein; Models, Molecular; Molecular Sequence Data; Paramyxoviridae; Protein Conformation; Receptors, Virus; Sequence Alignment; Viruses
PubMed: 19342221
DOI: 10.1016/j.sbi.2009.02.013 -
Molekuliarnaia Biologiia 2018Preclinical studies demonstrate that a broad spectrum of human and animal malignant cells can be killed by oncolytic paramyxoviruses, which includes cells of ecto-,... (Review)
Review
Preclinical studies demonstrate that a broad spectrum of human and animal malignant cells can be killed by oncolytic paramyxoviruses, which includes cells of ecto-, endo- and mesodermal origin. In clinical trials, significant reduction or even complete elimination of primary tumors and established metastases has been reported. Different routes of virus administration (intratumoral, intravenous, intradermal, intraperito-neal, or intrapleural) and single- vs. multiple-dose administration schemes have been explored. The reported side effects were grades 1 and 2, with the most common among them being mild fever. There are certain advantages in using paramyxoviruses as oncolytic agents compared to members of other virus families exist. Thanks to cytoplasmic replication, paramyxoviruses do not integrate the host genome or engage in recombination, which makes them safer and more attractive candidates for widely used therapeutic oncolysis than ret-roviruses or some DNA viruses. The list of oncolytic Paramyxoviridae members includes the attenuated measles virus, mumps virus, low pathogenic Newcastle disease, and Sendai viruses. Metastatic cancer cells frequently overexpress certain surface molecules that can serve as receptors for oncolytic paramyxoviruses. This promotes specific viral attachment to these malignant cells. Paramyxoviruses are capable of inducing efficient syncytium-mediated lysis of cancer cells and elicit strong immune stimulation, which dramatically enforces anticancer immune surveillance. In general, preclinical studies and phases I-III of clinical trials yield very encouraging results and warrant continued research of oncolytic paramyxoviruses as a particularly valuable addition to the existing panel of cancer-fighting approaches.
Topics: Animals; Humans; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Paramyxoviridae
PubMed: 29989571
DOI: 10.7868/S0026898418030023 -
Frontiers in Cellular and Infection... 2023Nipah virus (NiV) and Hendra virus (HeV) are newly emerging dangerous zoonotic pathogens of the genus of the family. NiV and HeV (HNVs) which are transmitted by bats...
Nipah virus (NiV) and Hendra virus (HeV) are newly emerging dangerous zoonotic pathogens of the genus of the family. NiV and HeV (HNVs) which are transmitted by bats cause acute respiratory disease and fatal encephalitis in humans. To date, as there is a lack of antiviral drugs or effective antiviral therapies, the development of vaccines against those two viruses is of primary importance, and the immunogen design is crucial to the success of vaccines. In this study, the full-length protein (G), the ectodomain (Ge) and the head domain (Gs) of NiV attachment glycoprotein were delivered by the replication-defective type 5 adenovirus vector (Ad5) respectively, and the recombinant Ad5-NiV vaccine candidates (Ad5-NiVG, Ad5-NiVGe and Ad5-NiVGs) were constructed and their immunogenicity were evaluated in mice. The results showed that all the vaccine candidates stimulated specific humoral and cellular immune responses efficiently and rapidly against both NiV and HeV, and the Ad5-NiVGe elicited the strongest immune responses after a single-dose immunization. Furthermore, the potent conserved T-cell epitope DTLYFPAVGFL shared by NiV and HeV was identified in the study, which may provide valid information on the mechanism of HNVs-specific cellular immunity. In summary, this study demonstrates that the Ad5-NiVGe could be a potent vaccine candidate against HNVs by inducing robust humoral and cellular immune responses.
Topics: Humans; Animals; Mice; Hendra Virus; Nipah Virus; Virus Attachment; Glycoproteins; Vaccines, Synthetic; Immunity, Cellular; Adenoviridae
PubMed: 37577376
DOI: 10.3389/fcimb.2023.1180344 -
Viruses Dec 2012Human metapneumovirus (hMPV) is a recently identified RNA virus belonging to the Paramyxoviridae family, which includes several major human and animal pathogens.... (Review)
Review
Human metapneumovirus (hMPV) is a recently identified RNA virus belonging to the Paramyxoviridae family, which includes several major human and animal pathogens. Epidemiological studies indicate that hMPV is a significant human respiratory pathogen with worldwide distribution. It is associated with respiratory illnesses in children, adults, and immunocompromised patients, ranging from upper respiratory tract infections to severe bronchiolitis and pneumonia. Interferon (IFN) represents a major line of defense against virus infection, and in response, viruses have evolved countermeasures to inhibit IFN production as well as IFN signaling. Although the strategies of IFN evasion are similar, the specific mechanisms by which paramyxoviruses inhibit IFN responses are quite diverse. In this review, we will present an overview of the strategies that hMPV uses to subvert cellular signaling in airway epithelial cells, the major target of infection, as well as in primary immune cells.
Topics: Humans; Immune Evasion; Immunity, Innate; Interferons; Metapneumovirus; Viral Proteins; Virulence Factors
PubMed: 23223197
DOI: 10.3390/v4123551 -
Cellular and Molecular Life Sciences :... Sep 2017In this review, we summarize computational and experimental data gathered so far showing that structural disorder is abundant within paramyxoviral nucleoproteins (N) and... (Review)
Review
In this review, we summarize computational and experimental data gathered so far showing that structural disorder is abundant within paramyxoviral nucleoproteins (N) and phosphoproteins (P). In particular, we focus on measles, Nipah, and Hendra viruses and highlight both commonalities and differences with respect to the closely related Sendai virus. The molecular mechanisms that control the disorder-to-order transition undergone by the intrinsically disordered C-terminal domain (N) of their N proteins upon binding to the C-terminal X domain (XD) of the homologous P proteins are described in detail. By having a significant residual disorder, N-XD complexes are illustrative examples of "fuzziness", whose possible functional significance is discussed. Finally, the relevance of N-P interactions as promising targets for innovative antiviral approaches is underscored, and the functional advantages of structural disorder for paramyxoviruses are pinpointed.
Topics: Antiviral Agents; Evolution, Molecular; Intrinsically Disordered Proteins; Molecular Chaperones; Nucleoproteins; Paramyxoviridae; Phosphoproteins; Protein Structure, Quaternary; RNA, Viral; Viral Proteins; Virus Replication
PubMed: 28600653
DOI: 10.1007/s00018-017-2556-3 -
Journal of Molecular Biology Dec 2013Paramyxoviruses represent a remarkably diverse family of enveloped nonsegmented negative-strand RNA viruses, some of which are the most ubiquitous disease-causing... (Review)
Review
Paramyxoviruses represent a remarkably diverse family of enveloped nonsegmented negative-strand RNA viruses, some of which are the most ubiquitous disease-causing viruses of humans and animals. This review focuses on paramyxovirus activation of innate immune pathways, the mechanisms by which these RNA viruses counteract these pathways, and the innate response to paramyxovirus infection of dendritic cells (DC). Paramyxoviruses are potent activators of extracellular complement pathways, a first line of defense that viruses must face during natural infections. We discuss mechanisms by which these viruses activate and combat complement to delay neutralization. Once cells are infected, virus replication drives type I interferon (IFN) synthesis that has the potential to induce a large number of antiviral genes. Here we describe four approaches by which paramyxoviruses limit IFN induction: by limiting synthesis of IFN-inducing aberrant viral RNAs, through targeted inhibition of RNA sensors, by providing viral decoy substrates for cellular kinase complexes, and through direct blocking of the IFN promoter. In addition, paramyxoviruses have evolved diverse mechanisms to disrupt IFN signaling pathways. We describe three general mechanisms, including targeted proteolysis of signaling factors, sequestering cellular factors, and upregulation of cellular inhibitors. DC are exceptional cells with the capacity to generate adaptive immunity through the coupling of innate immune signals and T cell activation. We discuss the importance of innate responses in DC following paramyxovirus infection and their consequences for the ability to mount and maintain antiviral T cells.
Topics: Animals; Complement Activation; Complement Inactivator Proteins; Dendritic Cells; Genome, Viral; Host-Pathogen Interactions; Humans; Immunity, Innate; Interferon Type I; Lymphocyte Activation; Models, Molecular; Paramyxoviridae; Paramyxoviridae Infections; RNA, Viral; Signal Transduction; T-Lymphocytes; Viral Proteins; Virus Activation; Virus Replication
PubMed: 24056173
DOI: 10.1016/j.jmb.2013.09.015 -
Frontiers in Bioscience (Landmark... Jan 2013Matrix proteins are essential components of most negative-sense RNA, enveloped viruses. They serve a wide range of duties ranging from self-driven membrane budding and... (Review)
Review
Matrix proteins are essential components of most negative-sense RNA, enveloped viruses. They serve a wide range of duties ranging from self-driven membrane budding and coordination of other viral components to modulation of viral transcription. The functional similarity between these proteins is striking, despite major differences in their structures. Whereas biochemical and structural studies have partly been hindered by the inherent aggregation properties of these proteins, their cellular functions are beginning to be understood. In this review we summarize the current knowledge on negative-sense RNA virus matrix proteins and their interactions with other viral and cellular proteins. We also discuss the similarities and differences in matrix protein functions between the different families within the negative-sense RNA viruses.
Topics: Arenaviridae; Borna disease virus; Bunyaviridae; Filoviridae; Models, Molecular; Orthomyxoviridae; Paramyxoviridae; Rhabdoviridae; Viral Matrix Proteins; Virion
PubMed: 23276954
DOI: 10.2741/4132 -
Journal of Molecular Evolution Feb 2008Paramyxoviruses are responsible for considerable disease burden in human and wildlife populations: measles and mumps continue to affect the health of children worldwide,...
Paramyxoviruses are responsible for considerable disease burden in human and wildlife populations: measles and mumps continue to affect the health of children worldwide, while canine distemper virus causes serious morbidity and mortality in a wide range of mammalian species. Although these viruses have been studied extensively at both the epidemiological and the phylogenetic scales, little has been done to integrate these two types of data. Using a Bayesian coalescent approach, we infer the evolutionary and epidemiological dynamics of measles, mumps and canine distemper viruses. Our analysis yielded data on viral substitution rates, the time to common ancestry, and elements of their demographic history. Estimates of rates of evolutionary change were similar to those observed in other RNA viruses, ranging from 6.585 to 11.350 x 10(-4 )nucleotide substitutions per site, per year. Strikingly, the mean Time to the Most Recent Common Ancestor (TMRCA) was both similar and very recent among the viruses studied, ranging from only 58 to 91 years (1908 to 1943). Worldwide, the paramyxoviruses studied here have maintained a relatively constant level of genetic diversity. However, detailed heterchronous samples illustrate more complex dynamics in some epidemic populations, and the relatively low levels of genetic diversity (population size) in all three viruses is likely to reflect the population bottlenecks that follow recurrent outbreaks.
Topics: Animals; Capsid Proteins; Disease Outbreaks; Distemper Virus, Canine; Evolution, Molecular; Genetic Variation; HN Protein; Humans; Measles virus; Mumps virus; Nucleocapsid Proteins; Paramyxoviridae; Paramyxoviridae Infections; Phylogeny; Selection, Genetic
PubMed: 18217182
DOI: 10.1007/s00239-007-9040-x -
Biomolecules Mar 2023The protein C is a small viral protein encoded in an overlapping frame of the P gene in the subfamily Orthoparamyxovirinae. This protein, expressed by alternative...
The protein C is a small viral protein encoded in an overlapping frame of the P gene in the subfamily Orthoparamyxovirinae. This protein, expressed by alternative translation initiation, is a virulence factor that regulates viral transcription, replication, and production of defective interfering RNA, interferes with the host-cell innate immunity systems and supports the assembly of viral particles and budding. We expressed and purified full-length and an N-terminally truncated C protein from Tupaia paramyxovirus (TupV) C protein (genus Narmovirus). We solved the crystal structure of the C-terminal part of TupV C protein at a resolution of 2.4 Å and found that it is structurally similar to Sendai virus C protein, suggesting that despite undetectable sequence conservation, these proteins are homologous. We characterized both truncated and full-length proteins by SEC-MALLS and SEC-SAXS and described their solution structures by ensemble models. We established a mini-replicon assay for the related Nipah virus (NiV) and showed that TupV C inhibited the expression of NiV minigenome in a concentration-dependent manner as efficiently as the NiV C protein. A previous study found that the Orthoparamyxovirinae C proteins form two clusters without detectable sequence similarity, raising the question of whether they were homologous or instead had originated independently. Since TupV C and SeV C are representatives of these two clusters, our discovery that they have a similar structure indicates that all Orthoparamyxovirine C proteins are homologous. Our results also imply that, strikingly, a STAT1-binding site is encoded by exactly the same RNA region of the P/C gene across Paramyxovirinae, but in different reading frames (P or C), depending on which cluster they belong to.
Topics: Scattering, Small Angle; X-Ray Diffraction; Nipah Virus; Immunity, Innate; RNA
PubMed: 36979390
DOI: 10.3390/biom13030455 -
Journal of Interferon & Cytokine... Sep 2009Experimentally, paramyxoviruses are conventionally considered good inducers of type I interferons (IFN-alpha/beta), and have been used as agents in the commercial... (Review)
Review
Experimentally, paramyxoviruses are conventionally considered good inducers of type I interferons (IFN-alpha/beta), and have been used as agents in the commercial production of human IFN-alpha. However, in the last few years it has become clear that viruses in general mount a major challenge to the IFN system, and paramyxoviruses are no exception. Indeed, most paramyxoviruses encode mechanisms to inhibit both the production of, and response to, type I IFN. Here we review our knowledge of the type I IFN-inducing signals (by so-called pathogen-associated molecular patterns, or PAMPs) produced during paramyxovirus infections, and discuss how paramyxoviruses limit the production of PAMPs and inhibit the cellular responses to PAMPs by interfering with the activities of the pattern recognition receptors (PRRs), mda-5, and RIG-I, as well as downstream components in the type I IFN induction cascades.
Topics: Animals; Antigens, Surface; DEAD-box RNA Helicases; GPI-Linked Proteins; Humans; Interferon Type I; Interferon-Induced Helicase, IFIH1; Membrane Proteins; Paramyxoviridae; Paramyxoviridae Infections; Receptors, Pattern Recognition; Recombinant Proteins; Signal Transduction
PubMed: 19702509
DOI: 10.1089/jir.2009.0071