-
Viruses Dec 2018The order harbors numerous viruses of significant relevance to human health, including both established and emerging infections. Currently, vaccines are only available... (Review)
Review
The order harbors numerous viruses of significant relevance to human health, including both established and emerging infections. Currently, vaccines are only available for a small subset of these viruses, and antiviral therapies remain limited. Being obligate cellular parasites, viruses must utilize the cellular machinery for their replication and spread. Therefore, targeting cellular pathways used by viruses can provide novel therapeutic approaches. One of the key challenges confronted by both hosts and viruses alike is the successful folding and maturation of proteins. In cells, this task is faced by cellular molecular chaperones, a group of conserved and abundant proteins that oversee protein folding and help maintain protein homeostasis. In this review, we summarize the current knowledge of how the interact with cellular chaperones, highlight key gaps in our knowledge, and discuss the potential of chaperone inhibitors as antivirals.
Topics: Antiviral Agents; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Host-Pathogen Interactions; Humans; Measles virus; Molecular Chaperones; Mononegavirales; Protein Folding; Respiratory Syncytial Viruses; Virus Replication
PubMed: 30544818
DOI: 10.3390/v10120699 -
Nature Communications Apr 2018Measles virus (MeV) remains a major human pathogen, but there are presently no licensed antivirals to treat MeV or other paramyxoviruses. Here, we use cryo-electron...
Measles virus (MeV) remains a major human pathogen, but there are presently no licensed antivirals to treat MeV or other paramyxoviruses. Here, we use cryo-electron tomography (cryo-ET) to elucidate the principles governing paramyxovirus assembly in MeV-infected human cells. The three-dimensional (3D) arrangement of the MeV structural proteins including the surface glycoproteins (F and H), matrix protein (M), and the ribonucleoprotein complex (RNP) are characterized at stages of virus assembly and budding, and in released virus particles. The M protein is observed as an organized two-dimensional (2D) paracrystalline array associated with the membrane. A two-layered F-M lattice is revealed suggesting that interactions between F and M may coordinate processes essential for MeV assembly. The RNP complex remains associated with and in close proximity to the M lattice. In this model, the M lattice facilitates the well-ordered incorporation and concentration of the surface glycoproteins and the RNP at sites of virus assembly.
Topics: Cell Line; Cryoelectron Microscopy; Fibroblasts; HeLa Cells; Hemagglutinins, Viral; Humans; Measles virus; Ribonucleoproteins; Viral Fusion Proteins; Viral Matrix Proteins; Virion; Virus Assembly; Virus Release
PubMed: 29712906
DOI: 10.1038/s41467-018-04058-2 -
Journal of Medical Virology Oct 2022Measles, caused by measles virus (MeV), has not been eradicated in many regions and countries, threatening human health. Thus, it is beneficial for measles elimination...
Measles, caused by measles virus (MeV), has not been eradicated in many regions and countries, threatening human health. Thus, it is beneficial for measles elimination to understand measles epidemiology and molecular evolution of key viral genes, such as nucleoprotein (N) gene. Based on public data, measles epidemiological information and MeV N gene sequences reported in Shandong Province, China were comprehensively collected and systematically analyzed. The results showed a positive correlation between population density and measles incidence (r = +0.31), while negative correlations were found between measles incidence and healthcare condition (r = -0.21) as well as average routine vaccination rate (r = -0.11). Additionally, the predominant lineage of MeV in Shandong was formed by genotype H1 strains, and the time of the most recent common ancestor of the N gene of MeV genotype H1 in Shandong traced back to 1987 (95% highest posterior density, 1984-1990) with relatively rapid evolution (mean rate, 1.267 × 10 substitutions/site/year). The genetic diversity of MeV N gene increased with the substantial emergence of major divergent clades of genotype H1 before 2005 and then remained relatively high and stable. In summary, these findings provided a significant insight into the measles elimination.
Topics: China; Genes, Viral; Genotype; Humans; Measles; Measles virus; Nucleocapsid Proteins; Nucleoproteins; Phylogeny
PubMed: 35711081
DOI: 10.1002/jmv.27941 -
Biomolecules Dec 2018In this paper we review our recent findings on the different interaction mechanisms of the C-terminal domain of the nucleoprotein (N) of measles virus (MeV) N, a model... (Review)
Review
In this paper we review our recent findings on the different interaction mechanisms of the C-terminal domain of the nucleoprotein (N) of measles virus (MeV) N, a model viral intrinsically disordered protein (IDP), with two of its known binding partners, i.e., the C-terminal X domain of the phosphoprotein of MeV XD (a globular viral protein) and the heat-shock protein 70 hsp70 (a globular cellular protein). The N binds both XD and hsp70 via a molecular recognition element (MoRE) that is flanked by two fuzzy regions. The long (85 residues) N-terminal fuzzy region is a natural dampener of the interaction with both XD and hsp70. In the case of binding to XD, the N-terminal fuzzy appendage of N reduces the rate of α-helical folding of the MoRE. The dampening effect of the fuzzy appendage on XD and hsp70 binding depends on the length and fuzziness of the N-terminal region. Despite this similarity, N binding to XD and hsp70 appears to rely on completely different requirements. Almost any mutation within the MoRE decreases XD binding, whereas many of them increase the binding to hsp70. In addition, XD binding is very sensitive to the α-helical state of the MoRE, whereas hsp70 is not. Thus, contrary to hsp70, XD binding appears to be strictly dependent on the wild-type primary and secondary structure of the MoRE.
Topics: Amino Acid Sequence; Binding Sites; HSP70 Heat-Shock Proteins; Humans; Measles virus; Mutagenesis; Nucleocapsid Proteins; Nucleoproteins; Phosphoproteins; Protein Binding; Protein Structure, Secondary; Viral Proteins
PubMed: 30591682
DOI: 10.3390/biom9010008 -
Biomedica : Revista Del Instituto... Apr 2017Introducción. El virus del Zika (ZIKV) es un flavivirus con envoltura, transmitido a los seres humanos principalmente por el vector Aedes aegypti. La infección por...
Introducción. El virus del Zika (ZIKV) es un flavivirus con envoltura, transmitido a los seres humanos principalmente por el vector Aedes aegypti. La infección por ZIKV se ha asociado con un gran neurotropismo y con efectos neuropáticos, como el síndrome de Guillain-Barré en el adulto y la microcefalia fetal y posnatal, así como con un síndrome de infección congénita similar al producido por el virus de la rubéola (RV).Objetivo. Comparar las estructuras moleculares de la proteína de envoltura E del virus del Zika (E-ZIKV) y de la E1 del virus de la rubéola (E1-RV), y plantear posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso asociadas con el ZIKV.Materiales y métodos. La secuencia de aminoácidos de la proteína E-ZIKV (PDB: 5iZ7) se alineó con la de la glucopreteína E1 del virus de la rubéola (PDB: 4ADG). Los elementos de la estructura secundaria se determinaron usando los programas Vector NTI Advance®, DSSP y POSA, así como herramientas de gestión de datos (AlignX®). Uno de los criterios principales de comparación y alineación fue la asignación de residuos estructuralmente equivalentes, con más de 70 % de identidad.Resultados. La organización estructural de la proteína E-ZIKV (PDB: 5iZ7) fue similar a la de E1-RV (PDB: 4ADG) (70 a 80 % de identidad), y se observó una correspondencia con la estructura definida para las glucoproteínas de fusión de membrana de clase II de los virus con envoltura. E-ZIKV y E1-RV exhibieron elementos estructurales de fusión muy conservados en la región distal del dominio II, asociados con la unión a los receptores celulares de entrada del virus de la rubéola (glucoproteína de mielina del oligodendrocito, Myelin Oligodendrocyte Glycoprotein, MOG), y con los receptores celulares Axl del ZIKV y de otros flavivirus.Conclusión. La comparación de las proteínas E-ZIKV y E1-RV es un paso necesario hacia la definición de otros factores moleculares determinantes del neurotropismo y la patogenia del ZIKV, el cual puede contribuir a generar estrategias de diagnóstico, prevención y tratamiento de las complicaciones neurológicas inducidas por el ZIKV.
Topics: Humans; Measles virus; Molecular Biology; Serine Endopeptidases; Viral Envelope Proteins; Viral Proteins; Zika Virus
PubMed: 28527274
DOI: 10.7705/biomedica.v37i0.3807 -
The Journal of Infection Sep 2021We attempted to establish a molecular investigation by Next Generation sequencing of the measles virus (MeV) strains circulating in Marseille-France during the last...
OBJECTIVES
We attempted to establish a molecular investigation by Next Generation sequencing of the measles virus (MeV) strains circulating in Marseille-France during the last outbreak that occurred between 2017 and 2019.
METHODS
The circulating MeV were isolated from clinical samples using cell culture method and whole genomes were sequenced by Illumina Miseq Next Generation. Genotyping and comparative analyses were assessed by phylogenetic reconstructions. Clinical and epidemiological data from cases were also recorded.
RESULTS
A total of 110 MeV strains were isolated in cell culture. Our analysis based on whole genome sequences of 98 isolates confirmed that 93 strains belonged to the genotype D8 and 5 to the genotype B3. Phylogenetic analyses revealed 4 distinct MeV circulating clones in Marseille. Measles mostly occured in children < 5 years-old and in adults 30-50 years-old. Measles infection also occurred in 2 adequately vaccinated cases (2 doses). Among 63 measles cases of whom we had available clinical data informations, a total of 35 patients were hospitalized and 19 developed complications including one death case recorded.
CONCLUSIONS
Whole Genome Sequencing seems to be a useful tool for more refined genomic characterization of large measles outbreak. Vaccination strategies for measles eradication need to be re-evaluated in the current context.
Topics: Adult; Child, Preschool; Disease Outbreaks; France; Genotype; Humans; Measles; Measles virus; Middle Aged; Phylogeny
PubMed: 34310945
DOI: 10.1016/j.jinf.2021.07.011 -
Clinical Infectious Diseases : An... May 2021Prolonged measles virus detection in maternal saliva and blood was evidenced in 6 pregnant women. Maternal-fetal transmission was evidenced in 2 of 4 infants who were...
Prolonged measles virus detection in maternal saliva and blood was evidenced in 6 pregnant women. Maternal-fetal transmission was evidenced in 2 of 4 infants who were asymptomatic at birth, 21-24 weeks after maternal infection. Whereas peripartum congenital measles is severe, asymptomatic measles virus vertical transmission can occur earlier in pregnancy.
Topics: Female; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Measles; Measles virus; Parturition; Pregnancy; Pregnancy Complications, Infectious
PubMed: 32614433
DOI: 10.1093/cid/ciaa915 -
Nature Communications Feb 2024Measles cases have surged pre-COVID-19 and the pandemic has aggravated the problem. Most measles-associated morbidity and mortality arises from destruction of...
Measles cases have surged pre-COVID-19 and the pandemic has aggravated the problem. Most measles-associated morbidity and mortality arises from destruction of pre-existing immune memory by measles virus (MeV), a paramyxovirus of the morbillivirus genus. Therapeutic measles vaccination lacks efficacy, but little is known about preserving immune memory through antivirals and the effect of respiratory disease history on measles severity. We use a canine distemper virus (CDV)-ferret model as surrogate for measles and employ an orally efficacious paramyxovirus polymerase inhibitor to address these questions. A receptor tropism-intact recombinant CDV with low lethality reveals an 8-day advantage of antiviral treatment versus therapeutic vaccination in maintaining immune memory. Infection of female ferrets with influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks pre-CDV causes fatal hemorrhagic pneumonia with lung onslaught by commensal bacteria. RNAseq identifies CDV-induced overexpression of trefoil factor (TFF) peptides in the respiratory tract, which is absent in animals pre-infected with IAV. Severe outcomes of consecutive IAV/CDV infections are mitigated by oral antivirals even when initiated late. These findings validate the morbillivirus immune amnesia hypothesis, define measles treatment paradigms, and identify priming of the TFF axis through prior respiratory infections as risk factor for exacerbated morbillivirus disease.
Topics: Animals; Female; Ferrets; Influenza A Virus, H1N1 Subtype; Measles; Measles virus; Distemper Virus, Canine; Antiviral Agents
PubMed: 38331906
DOI: 10.1038/s41467-024-45418-5 -
FEBS Letters Sep 2015In this review I summarize available data pointing to the abundance of structural disorder within the nucleoprotein (N) from three paramyxoviruses, namely the measles... (Review)
Review
In this review I summarize available data pointing to the abundance of structural disorder within the nucleoprotein (N) from three paramyxoviruses, namely the measles (MeV), Nipah (NiV) and Hendra (HeV) viruses. I provide a detailed description of the molecular mechanisms that govern the disorder-to-order transition that the intrinsically disordered C-terminal domain (NTAIL) of their N proteins undergoes upon binding to the C-terminal X domain (XD) of the homologous phosphoproteins. I also show that a significant flexibility persists within NTAIL-XD complexes, which makes them illustrative examples of "fuzziness". Finally, I discuss the functional implications of structural disorder for viral transcription and replication in light of the promiscuity of disordered regions and of the considerable reach they confer to the components of the replicative machinery.
Topics: Hendra Virus; Intrinsically Disordered Proteins; Measles virus; Models, Molecular; Nipah Virus; Nucleocapsid Proteins; Pliability; Protein Binding; Protein Folding; Protein Structure, Tertiary
PubMed: 26071376
DOI: 10.1016/j.febslet.2015.05.055 -
Journal of Virological Methods Apr 2022The use of oncolytic viruses (OV) to precisely target and eliminate tumors ('virotherapy') is a rapidly evolving therapeutic approach to treating cancer. A major...
The use of oncolytic viruses (OV) to precisely target and eliminate tumors ('virotherapy') is a rapidly evolving therapeutic approach to treating cancer. A major obstacle in virotherapy, especially for systemic administration, is the host's immune response towards the OV. In the case of measles virus (MeV), most individuals have been immunized against this agent leading to pre-existing neutralizing antibodies that can impair OV delivery to the tumor. These antibodies predominantly target the hemagglutinin (H) and fusion (F) envelope glycoproteins displayed at the particle's surface. Here, we introduce a novel and versatile pseudotyping platform for rapid envelope exchange of oncolytic MeV that allows for engineering of chimeric viruses invulnerable to pre-existing anti-MeV antibodies. Using this system, we have successfully exchanged the MeV F and H proteins with the glycoprotein G of vesicular stomatitis virus (VSV) and the surface proteins of Newcastle disease virus (NDV) or canine distemper virus (CDV), all of which are not endemic in the general human population. While the MeV-VSV and MeV-NDV pseudotypes were non-functional, the MeV-CDV pseudotype was successfully propagated to high-titer virus stocks. This study describes the successful generation of a robust envelope exchange platform for oncolytic MeV while also highlighting its intricate pseudotyping tolerance.
Topics: Animals; Antibodies, Neutralizing; Measles virus; Oncolytic Virotherapy; Oncolytic Viruses; Vesicular stomatitis Indiana virus
PubMed: 35104497
DOI: 10.1016/j.jviromet.2022.114487