scholarly journals Structure and stabilization of the Hendra virus F glycoprotein in its prefusion form

2015 ◽  
Vol 113 (4) ◽  
pp. 1056-1061 ◽  
Author(s):  
Joyce J. W. Wong ◽  
Reay G. Paterson ◽  
Robert A. Lamb ◽  
Theodore S. Jardetzky
Keyword(s):  
Nipah Virus ◽  
Fusion Peptide ◽  
Hendra Virus ◽  
Cell Entry ◽  
Loss Of Function ◽  
Host Cell Membrane ◽  
Peptide Cleavage ◽  
Apical Loop ◽  
The Stability ◽  
Biosafety Level

Hendra virus (HeV) is one of the two prototypical members of theHenipavirusgenus of paramyxoviruses, which are designated biosafety level 4 (BSL-4) organisms due to the high mortality rate of Nipah virus (NiV) and HeV in humans. Paramyxovirus cell entry is mediated by the fusion protein, F, in response to binding of a host receptor by the attachment protein. During posttranslational processing, the fusion peptide of F is released and, upon receptor-induced triggering, inserts into the host cell membrane. As F undergoes a dramatic refolding from its prefusion to postfusion conformation, the fusion peptide brings the host and viral membranes together, allowing entry of the viral RNA. Here, we present the crystal structure of the prefusion form of the HeV F ectodomain. The structure shows very high similarity to the structure of prefusion parainfluenza virus 5 (PIV5) F, with the main structural differences in the membrane distal apical loops and the fusion peptide cleavage loop. Functional assays of mutants show that the apical loop can tolerate perturbation in length and surface residues without loss of function, except for residues involved in the stability and conservation of the F protein fold. Structure-based disulfide mutants were designed to anchor the fusion peptide to conformationally invariant residues of the F head. Two mutants were identified that inhibit F-mediated fusion by stabilizing F in its prefusion conformation.

Henipavirus Infections - An Expanding Zoonosis from Fruit Bats

2011 ◽  
Vol 6 (4) ◽  
pp. 390-397 ◽  
Author(s):  
Chieko Kai ◽  
◽  
Misako Yoneda
Keyword(s):  
South Asia ◽  
Nipah Virus ◽  
Economic Loss ◽  
Hendra Virus ◽  
Basic Knowledge ◽  
Fatality Rate ◽  
Fruit Bats ◽  
Fruit Bat ◽  
Natural Virus ◽  
Biosafety Level

The henipavirus genus has two members – the Hendra virus (HeV) and the Nipah virus (NiV). HeV and NiV, identified in the 1990s as a paramyxovirus, cause fatalities in humans and animals. They are now classified as biosafety level 4 pathogens. HeV caused fatal respiratory infection in horses and humans in Australia in 1994, in which 2 persons died. The first-known, largest NiV outbreak occurred on theMalay Peninsula in 1998, in pigs and humans. The human fatality rate was 40%, killing 105. To cope, the Malaysian government culled over 1 million pigs at huge economic loss. The natural virus reservoir, the fruit bat (Pteropus), inhabits areas from Australia, through South Asia to Africa. InMalaysia, NiV to humans was through pigs, and the reemergence has never observed after that. However, sporadic outbreaks of NiV are continuously occurring in Bangladesh and India, in some of which epidemics human mortality exceeds 75%. The transmission is directly from fruit bats to humans, and even human-to-human transmissions are found. To prevent the outbreaks, it is important to have an intense monitoring for these diseases, to accumulate basic knowledge about the viruses and the diseases, and to develop effective vaccines.

scholarly journals Chloroquine Administration Does Not Prevent Nipah Virus Infection and Disease in Ferrets

2009 ◽  
Vol 83 (22) ◽  
pp. 11979-11982 ◽  
Author(s):  
Jackie Pallister ◽  
Deborah Middleton ◽  
Gary Crameri ◽  
Manabu Yamada ◽  
Reuben Klein ◽  
...  
Keyword(s):  
Virus Infection ◽  
Nipah Virus ◽  
Disease Outbreaks ◽  
Mortality Rates ◽  
Hendra Virus ◽  
Malaria Therapy ◽  
Sporadic Disease

ABSTRACT Hendra virus and Nipah virus, two zoonotic paramyxoviruses in the genus Henipavirus, have recently emerged and continue to cause sporadic disease outbreaks in humans and animals. Mortality rates of up to 75% have been reported in humans, but there are presently no clinically licensed therapeutics for treating henipavirus-induced disease. A recent report indicated that chloroquine, used in malaria therapy for over 70 years, prevented infection with Nipah virus in vitro. Chloroquine was assessed using a ferret model of lethal Nipah virus infection and found to be ineffective against Nipah virus infection in vivo.

scholarly journals From The Cover: Ephrin-B2 ligand is a functional receptor for Hendra virus and Nipah virus

2005 ◽  
Vol 102 (30) ◽  
pp. 10652-10657 ◽  
Author(s):  
M. I. Bonaparte ◽  
A. S. Dimitrov ◽  
K. N. Bossart ◽  
G. Crameri ◽  
B. A. Mungall ◽  
...  
Keyword(s):  
Nipah Virus ◽  
Hendra Virus ◽  
Functional Receptor

scholarly journals Hendra and Nipah Virus Infection in Cultured Human Olfactory Epithelial Cells

mSphere ◽  
2017 ◽  
Vol 2 (3) ◽  
Author(s):  
Viktoriya Borisevich ◽  
Mehmet Hakan Ozdener ◽  
Bilal Malik ◽  
Barry Rockx
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Olfactory Epithelium ◽  
Neurological Disease ◽  
Nipah Virus ◽  
Hendra Virus ◽  
Olfactory Neurons ◽  
Zoonotic Pathogens ◽  
The Central Nervous System ◽  
A Site

ABSTRACT Henipaviruses are emerging zoonotic pathogens that can cause acute and severe respiratory and neurological disease in humans. The pathways by which henipaviruses enter the central nervous system (CNS) in humans are still unknown. The observation that human olfactory neurons are highly susceptible to infection with henipaviruses demonstrates that the olfactory epithelium can serve as a site of Henipavirus entry into the CNS. Henipaviruses are emerging zoonotic viruses and causative agents of encephalitis in humans. However, the mechanisms of entry into the central nervous system (CNS) in humans are not known. Here, we evaluated the possible role of olfactory epithelium in virus entry into the CNS. We characterized Hendra virus (HeV) and Nipah virus (NiV) infection of primary human olfactory epithelial cultures. We show that henipaviruses can infect mature olfactory sensory neurons. Henipaviruses replicated efficiently, resulting in cytopathic effect and limited induction of host responses. These results show that human olfactory epithelium is susceptible to infection with henipaviruses, suggesting that this could be a pathway for neuroinvasion in humans. IMPORTANCE Henipaviruses are emerging zoonotic pathogens that can cause acute and severe respiratory and neurological disease in humans. The pathways by which henipaviruses enter the central nervous system (CNS) in humans are still unknown. The observation that human olfactory neurons are highly susceptible to infection with henipaviruses demonstrates that the olfactory epithelium can serve as a site of Henipavirus entry into the CNS.

scholarly journals Dysbindin deficiency Alters Cardiac BLOC-1 Complex and Myozap Levels in Mice

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2390
Author(s):  
Ankush Borlepawar ◽  
Nesrin Schmiedel ◽  
Matthias Eden ◽  
Lynn Christen ◽  
Alexandra Rosskopf ◽  
...  
Keyword(s):  
Direct Interaction ◽  
Cardiomyocyte Hypertrophy ◽  
Loss Of Function ◽  
Interaction Partners ◽  
Lysosome Related Organelles ◽  
The Stability ◽  
Schizophrenia Susceptibility

Dysbindin, a schizophrenia susceptibility marker and an essential constituent of BLOC-1 (biogenesis of lysosome-related organelles complex-1), has recently been associated with cardiomyocyte hypertrophy through the activation of Myozap-RhoA-mediated SRF signaling. We employed sandy mice (Dtnbp1_KO), which completely lack Dysbindin protein because of a spontaneous deletion of introns 5–7 of the Dtnbp1 gene, for pathophysiological characterization of the heart. Unlike in vitro, the loss-of-function of Dysbindin did not attenuate cardiac hypertrophy, either in response to transverse aortic constriction stress or upon phenylephrine treatment. Interestingly, however, the levels of hypertrophy-inducing interaction partner Myozap as well as the BLOC-1 partners of Dysbindin like Muted and Pallidin were dramatically reduced in Dtnbp1_KO mouse hearts. Taken together, our data suggest that Dysbindin’s role in cardiomyocyte hypertrophy is redundant in vivo, yet essential to maintain the stability of its direct interaction partners like Myozap, Pallidin and Muted.

scholarly journals Microsphere Suspension Array Assays for Detection and Differentiation of Hendra and Nipah Viruses

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Adam J. Foord ◽  
John R. White ◽  
Axel Colling ◽  
Hans G. Heine
Keyword(s):  
Human Health ◽  
Virus Type ◽  
Nipah Virus ◽  
Hendra Virus ◽  
Diagnostic Specificity ◽  
Suspension Array ◽  
Specificity And Sensitivity ◽  
Nucleoprotein N ◽  
Encoding Genes ◽  
Single Reaction

Microsphere suspension array systems enable the simultaneous fluorescent identification of multiple separate nucleotide targets in a single reaction. We have utilized commercially available oligo-tagged microspheres (Luminex MagPlex-TAG) to construct and evaluate multiplexed assays for the detection and differentiation of Hendra virus (HeV) and Nipah virus (NiV). Both these agents are bat-borne zoonotic paramyxoviruses of increasing concern for veterinary and human health. Assays were developed targeting multiple sites within the nucleoprotein (N) and phosphoprotein (P) encoding genes. The relative specificities and sensitivities of the assays were determined using reference isolates of each virus type, samples from experimentally infected horses, and archival veterinary diagnostic submissions. Results were assessed in direct comparison with an established qPCR. The microsphere array assays achieved unequivocal differentiation of HeV and NiV and the sensitivity of HeV detection was comparable to qPCR, indicating high analytical and diagnostic specificity and sensitivity.

scholarly journals Inhibition of henipavirus infection by Nipah virus attachment glycoprotein occurs without cell-surface downregulation of ephrin-B2 or ephrin-B3

2007 ◽  
Vol 88 (2) ◽  
pp. 582-591 ◽  
Author(s):  
Bevan Sawatsky ◽  
Allen Grolla ◽  
Nina Kuzenko ◽  
Hana Weingartl ◽  
Markus Czub
Keyword(s):  
Cell Surface ◽  
Nipah Virus ◽  
Functional Expression ◽  
Hendra Virus ◽  
Pcr Analysis ◽  
Protein G ◽  
Attachment Protein ◽  
Genetic Characteristics ◽  
Virus Attachment ◽  
Fusion Inhibition

Nipah virus (NiV) and Hendra virus (HeV) are newly identified members of the family Paramyxoviridae and have been classified in the new genus Henipavirus based on unique genetic characteristics distinct from other paramyxoviruses. Transgenic cell lines were generated that expressed either the attachment protein (G) or the fusion protein (F) of NiV. Functional expression of NiV F and G was verified by complementation with the corresponding glycoprotein, which resulted in the development of syncytia. When exposed to NiV and HeV, expression of NiV G in Crandall feline kidney cells resulted in a qualitative inhibition of both cytopathic effect (CPE) and cell death by both viruses. RT-PCR analysis of surviving exposed cells showed a complete absence of viral positive-sense mRNA and genomic negative-sense viral RNA. Cells expressing NiV G were also unable to fuse with cells co-expressing NiV F and G in a fluorescent fusion inhibition assay. Cell-surface staining for the cellular receptors for NiV and HeV (ephrin-B2 and ephrin-B3) indicated that they were located on the surface of cells, regardless of NiV G expression or infection by NiV. These results indicated that viral interference can be established for henipaviruses and requires only the expression of the attachment protein, G. Furthermore, it was found that this interference probably occurs at the level of virus entry, as fusion was not observed in cells expressing NiV G. Finally, expression of NiV G by either transient transfection or NiV infection did not alter the cell-surface levels of the two known viral receptors.

scholarly journals Determination of the henipavirus phosphoprotein gene mRNA editing frequencies and detection of the C, V and W proteins of Nipah virus in virus-infected cells

2009 ◽  
Vol 90 (2) ◽  
pp. 398-404 ◽  
Author(s):  
Michael K. Lo ◽  
Brian H. Harcourt ◽  
Bruce A. Mungall ◽  
Azaibi Tamin ◽  
Mark E. Peeples ◽  
...  
Keyword(s):  
Nipah Virus ◽  
Hendra Virus ◽  
Mrna Editing ◽  
C Protein ◽  
Reading Frame ◽  
Frame Sequence ◽  
P Gene ◽  
Infected Cells ◽  
Phosphoprotein Gene

The henipaviruses, Nipah virus (NiV) and Hendra virus (HeV), are highly pathogenic zoonotic paramyxoviruses. Like many other paramyxoviruses, henipaviruses employ a process of co-transcriptional mRNA editing during transcription of the phosphoprotein (P) gene to generate additional mRNAs encoding the V and W proteins. The C protein is translated from the P mRNA, but in an alternate reading frame. Sequence analysis of multiple, cloned mRNAs showed that the mRNA editing frequencies of the P genes of the henipaviruses are higher than those reported for other paramyxoviruses. Antisera to synthetic peptides from the P, V, W and C proteins of NiV were generated to study their expression in infected cells. All proteins were detected in both infected cells and purified virions. In infected cells, the W protein was detected in the nucleus while P, V and C were found in the cytoplasm.

scholarly journals Identification of the Nuclear Export Signal and STAT-Binding Domains of the Nipah Virus V Protein Reveals Mechanisms Underlying Interferon Evasion

2004 ◽  
Vol 78 (10) ◽  
pp. 5358-5367 ◽  
Author(s):  
Jason J. Rodriguez ◽  
Cristian D. Cruz ◽  
Curt M. Horvath
Keyword(s):  
Amino Acids ◽  
Protein Interactions ◽  
Nuclear Export ◽  
Nipah Virus ◽  
Nuclear Export Signal ◽  
Hendra Virus ◽  
Nuclear Accumulation ◽  
V Protein ◽  
Binding Domains ◽  
Export Signal

ABSTRACT The V proteins of Nipah virus and Hendra virus have been demonstrated to bind to cellular STAT1 and STAT2 proteins to form high-molecular-weight complexes that inhibit interferon (IFN)-induced antiviral transcription by preventing STAT nuclear accumulation. Analysis of the Nipah virus V protein has revealed a region between amino acids 174 and 192 that functions as a CRM1-dependent nuclear export signal (NES). This peptide is sufficient to complement an export-defective human immunodeficiency virus Rev protein, and deletion and substitution mutagenesis revealed that this peptide is necessary for both V protein shuttling and cytoplasmic retention of STAT1 and STAT2 proteins. However, the NES is not required for V-dependent IFN signaling inhibition. IFN signaling is blocked primarily by interaction between Nipah virus V residues 100 to 160 and STAT1 residues 509 to 712. Interaction with STAT2 requires a larger Nipah virus V segment between amino acids 100 and 300, but deletion of residues 230 to 237 greatly reduced STAT2 coprecipitation. Further, V protein interactions with cellular STAT1 is a prerequisite for STAT2 binding, and sequential immunoprecipitations demonstrate that V, STAT1, and STAT2 can form a tripartite complex. These findings characterize essential regions for Henipavirus V proteins that represent potential targets for therapeutic intervention.

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