scholarly journals Crystal Structure and Carbohydrate Analysis of Nipah Virus Attachment Glycoprotein: a Template for Antiviral and Vaccine Design

2008 ◽  
Vol 82 (23) ◽  
pp. 11628-11636 ◽  
Author(s):  
Thomas A. Bowden ◽  
Max Crispin ◽  
David J. Harvey ◽  
A. Radu Aricescu ◽  
Jonathan M. Grimes ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Ebola Virus ◽  
Nipah Virus ◽  
Glycosylation Site ◽  
Hendra Virus ◽  
Molecular Surface ◽  
Spectrometric Analysis ◽  
Viral Attachment ◽  
Virus Attachment ◽  
Host Interaction

ABSTRACT Two members of the paramyxovirus family, Nipah virus (NiV) and Hendra virus (HeV), are recent additions to a growing number of agents of emergent diseases which use bats as a natural host. Identification of ephrin-B2 and ephrin-B3 as cellular receptors for these viruses has enabled the development of immunotherapeutic reagents which prevent virus attachment and subsequent fusion. Here we present the structural analysis of the protein and carbohydrate components of the unbound viral attachment glycoprotein of NiV glycoprotein (NiV-G) at a 2.2-Å resolution. Comparison with its ephrin-B2-bound form reveals that conformational changes within the envelope glycoprotein are required to achieve viral attachment. Structural differences are particularly pronounced in the 579-590 loop, a major component of the ephrin binding surface. In addition, the 236-245 loop is rather disordered in the unbound structure. We extend our structural characterization of NiV-G with mass spectrometric analysis of the carbohydrate moieties. We demonstrate that NiV-G is largely devoid of the oligomannose-type glycans that in viruses such as human immunodeficiency virus type 1 and Ebola virus influence viral tropism and the host immune response. Nevertheless, we find putative ligands for the endothelial cell lectin, LSECtin. Finally, by mapping structural conservation and glycosylation site positions from other members of the paramyxovirus family, we suggest the molecular surface involved in oligomerization. These results suggest possible pathways of virus-host interaction and strategies for the optimization of recombinant vaccines.

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 Ecological dynamics of emerging bat virus spillover

2015 ◽  
Vol 282 (1798) ◽  
pp. 20142124 ◽  
Author(s):  
Raina K. Plowright ◽  
Peggy Eby ◽  
Peter J. Hudson ◽  
Ina L. Smith ◽  
David Westcott ◽  
...  
Keyword(s):  
Land Use ◽  
Ebola Virus ◽  
Land Use Changes ◽  
Nipah Virus ◽  
Reservoir Host ◽  
Hendra Virus ◽  
Marburg Virus ◽  
Virus Shedding ◽  
Viral Shedding ◽  
Reservoir Hosts

Viruses that originate in bats may be the most notorious emerging zoonoses that spill over from wildlife into domestic animals and humans. Understanding how these infections filter through ecological systems to cause disease in humans is of profound importance to public health. Transmission of viruses from bats to humans requires a hierarchy of enabling conditions that connect the distribution of reservoir hosts, viral infection within these hosts, and exposure and susceptibility of recipient hosts. For many emerging bat viruses, spillover also requires viral shedding from bats, and survival of the virus in the environment. Focusing on Hendra virus, but also addressing Nipah virus, Ebola virus, Marburg virus and coronaviruses, we delineate this cross-species spillover dynamic from the within-host processes that drive virus excretion to land-use changes that increase interaction among species. We describe how land-use changes may affect co-occurrence and contact between bats and recipient hosts. Two hypotheses may explain temporal and spatial pulses of virus shedding in bat populations: episodic shedding from persistently infected bats or transient epidemics that occur as virus is transmitted among bat populations. Management of livestock also may affect the probability of exposure and disease. Interventions to decrease the probability of virus spillover can be implemented at multiple levels from targeting the reservoir host to managing recipient host exposure and susceptibility.

scholarly journals Single Amino Acid Changes in the Nipah and Hendra Virus Attachment Glycoproteins Distinguish EphrinB2 from EphrinB3 Usage

2007 ◽  
Vol 81 (19) ◽  
pp. 10804-10814 ◽  
Author(s):  
Oscar A. Negrete ◽  
David Chu ◽  
Hector C. Aguilar ◽  
Benhur Lee
Keyword(s):  
Brain Stem ◽  
Viral Entry ◽  
Nipah Virus ◽  
Chimeric Protein ◽  
Hendra Virus ◽  
Single Amino Acid ◽  
Virus Attachment ◽  
Receptor Usage ◽  
Binding Determinants ◽  
The Brain

ABSTRACT The henipaviruses, Nipah virus (NiV) and Hendra virus (HeV), are lethal emerging paramyxoviruses. EphrinB2 and ephrinB3 have been identified as receptors for henipavirus entry. NiV and HeV share similar cellular tropisms and likely use an identical receptor set, although a quantitative comparison of receptor usage by NiV and HeV has not been reported. Here we show that (i) soluble NiV attachment protein G (sNiV-G) bound to cell surface-expressed ephrinB3 with a 30-fold higher affinity than that of sHeV-G, (ii) NiV envelope pseudotyped reporter virus (NiVpp) entered ephrinB3-expressing cells much more efficiently than did HeV pseudotyped particles (HeVpp), and (iii) NiVpp but not HeVpp entry was inhibited efficiently by soluble ephrinB3. These data underscore the finding that NiV uses ephrinB3 more efficiently than does HeV. Henipavirus G chimeric protein analysis implicated residue 507 in the G ectodomain in efficient ephrinB3 usage. Curiously, alternative versions of published HeV-G sequences show variations at residue 507 that can clearly affect ephrinB3 but not ephrinB2 usage. We further defined surrounding mutations (W504A and E505A) that diminished ephrinB3-dependent binding and viral entry without compromising ephrinB2 receptor usage and another mutation (E533Q) that abrogated both ephrinB2 and -B3 usage. Our results suggest that ephrinB2 and -B3 binding determinants on henipavirus G are distinct and dissociable. Global expression analysis showed that ephrinB3, but not ephrinB2, is expressed in the brain stem. Thus, ephrinB3-mediated viral entry and pathology may underlie the severe brain stem neuronal dysfunction seen in fatal Nipah viral encephalitis. Characterizing the determinants of ephrinB2 versus -B3 usage will further our understanding of henipavirus pathogenesis.

scholarly journals A single dose investigational subunit vaccine for human use against Nipah virus and Hendra virus

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Thomas W. Geisbert ◽  
Kathryn Bobb ◽  
Viktoriya Borisevich ◽  
Joan B. Geisbert ◽  
Krystle N. Agans ◽  
...  
Keyword(s):  
Single Dose ◽  
Subunit Vaccine ◽  
Nipah Virus ◽  
Hendra Virus ◽  
Vaccine Formulation ◽  
Protein Subunit ◽  
Primate Model ◽  
Virus Attachment ◽  
A Subunit ◽  
Human Vaccine

AbstractNipah and Hendra viruses are highly pathogenic bat-borne paramyxoviruses recently included in the WHO Blueprint priority diseases list. A fully registered horse anti-Hendra virus subunit vaccine has been in use in Australia since 2012. Based on the same immunogen, the Hendra virus attachment glycoprotein ectodomain, a subunit vaccine formulation for use in people is now in a Phase I clinical trial. We report that a single dose vaccination regimen of this human vaccine formulation protects against otherwise lethal challenges of either Hendra or Nipah virus in a nonhuman primate model. The protection against the Nipah Bangladesh strain begins as soon as 7 days post immunization with low dose of 0.1 mg protein subunit. Our data suggest this human vaccine could be utilized as efficient emergency vaccine to disrupt potential spreading of Nipah disease in an outbreak setting.

scholarly journals REVIEW: REMDESIVIR AS A CANDIDATE FOR COVID-19 TREATMENT

2021 ◽  
Vol 6 (8) ◽  
pp. 161-172
Author(s):  
Iffah Anasia ◽  
Zulharmita Zulharmita ◽  
Ridho Asra
Keyword(s):  
Respiratory System ◽  
Ebola Virus ◽  
Nipah Virus ◽  
Antiviral Drug ◽  
Antiviral Agent ◽  
Hendra Virus ◽  
Direct Acting Antiviral ◽  
The Us ◽  
Syncytial Virus ◽  
Direct Acting

Remdesivir is the first drug that has been approved by the US Food and Drug Administration (FDA) for clinical use in hospitalized patients with COVID-19 disease. From several therapeutic options, Remdesivir is a direct-acting antiviral drug that has previously been tested against the Ebola virus, known to be effective and safe enough to inhibit the replication of SARS-CoV-2. Corona virus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus that attacks the respiratory system in humans, this virus can cause mild disorders of the respiratory system, severe lung infections, and even death. Remdesivir is a broad-spectrum antiviral agent that has previously shown antiviral activity against filoviruses (Ebola and Marburg viruses), coronaviruses (SARS-CoV, MERS-CoV, SARS CoV-2), paramyxoviruses (type III influenza virus, Nipah virus, Hendra virus, measles, and mumps virus) and Pnemoviriidae (respiratory syncytial virus).

scholarly journals Molecular Determinants of Antiviral Potency of Paramyxovirus Entry Inhibitors

2007 ◽  
Vol 81 (19) ◽  
pp. 10567-10574 ◽  
Author(s):  
M. Porotto ◽  
P. Carta ◽  
Y. Deng ◽  
G. E. Kellogg ◽  
M. Whitt ◽  
...  
Keyword(s):  
Glutamic Acid ◽  
Conformational Changes ◽  
Transmembrane Domain ◽  
Nipah Virus ◽  
Coiled Coil ◽  
Hendra Virus ◽  
Heptad Repeat ◽  
Protein Fusion ◽  
C Peptide ◽  
Entry Inhibitors

ABSTRACT Hendra virus (HeV) and Nipah virus (NiV) constitute the Henipavirus genus of paramyxoviruses, both fatal in humans and with the potential for subversion as agents of bioterrorism. Binding of the HeV/NiV attachment protein (G) to its receptor triggers a series of conformational changes in the fusion protein (F), ultimately leading to formation of a postfusion six-helix bundle (6HB) structure and fusion of the viral and cellular membranes. The ectodomain of paramyxovirus F proteins contains two conserved heptad repeat regions, the first (the N-terminal heptad repeat [HRN]) adjacent to the fusion peptide and the second (the C-terminal heptad repeat [HRC]) immediately preceding the transmembrane domain. Peptides derived from the HRN and HRC regions of F are proposed to inhibit fusion by preventing activated F molecules from forming the 6HB structure that is required for fusion. We previously reported that a human parainfluenza virus 3 (HPIV3) F peptide effectively inhibits infection mediated by the HeV glycoproteins in pseudotyped-HeV entry assays more effectively than the comparable HeV-derived peptide, and we now show that this peptide inhibits live-HeV and -NiV infection. HPIV3 F peptides were also effective in inhibiting HeV pseudotype virus entry in a new assay that mimics multicycle replication. This anti-HeV/NiV efficacy can be correlated with the greater potential of the HPIV3 C peptide to interact with the HeV F N peptide coiled-coil trimer, as evaluated by thermal unfolding experiments. Furthermore, replacement of a buried glutamic acid (glutamic acid 459) in the C peptide with valine enhances antiviral potency and stabilizes the 6HB conformation. Our results strongly suggest that conserved interhelical packing interactions in the F protein fusion core are important determinants of C peptide inhibitory activity and offer a strategy for the development of more-potent analogs of F peptide inhibitors.

scholarly journals Location of, immunogenicity of and relationships between neutralization epitopes on the attachment protein (G) of Hendra virus

2005 ◽  
Vol 86 (10) ◽  
pp. 2839-2848 ◽  
Author(s):  
John R. White ◽  
Victoria Boyd ◽  
Gary S. Crameri ◽  
Christine J. Duch ◽  
Ryan K. van Laar ◽  
...  
Keyword(s):  
Amino Acid ◽  
Measles Virus ◽  
Structural Model ◽  
Nipah Virus ◽  
Hendra Virus ◽  
Protein G ◽  
Head Region ◽  
Attachment Protein ◽  
Virus Attachment ◽  
Discontinuous Epitope

Epitopes involved in a protective immune response to Hendra virus (HeV) (Henipavirus, Paramxyoviridae) were investigated by generating five neutralizing monoclonal antibodies (mAbs) to the virus attachment protein (G) of HeV (HeV G) and sequencing of the G gene of groups of neutralization-escape variants selected with each mAb. Amino acid substitutions occurred at eight distinct sites on HeV G. Relationships between these sites were investigated in binding and neutralization assays using heterologous combinations of variants and mAbs. The sites were also mapped to a proposed structural model for the attachment proteins of Paramyxoviridae. Their specific locations and the nature of their interactions with the mAb panel provided the first functional evidence that HeV G in fact resembled the proposed structure. Four sites (aa 183–185, 417, 447 and 570) contributed to a major discontinuous epitope, on the base of the globular head, that was similar to immunodominant virus neutralization sites found in other paramyxoviruses. Amino acid similarity between HeV and Nipah virus was relatively highly conserved at these sites but decreased significantly at the other sites identified in this study. These included another discontinuous epitope on the base of the head region defined by sites aa 289 and 324 and well separated epitopes on the top of the head at sites aa 191–195 and 385–356. The latter epitope corresponded to immunodominant neutralization sites found in Rinderpest virus and Measles virus.

scholarly journals Bat-associated diseases

2017 ◽  
Vol 38 (1) ◽  
pp. 3
Author(s):  
Glenn A Marsh
Keyword(s):  
Infectious Diseases ◽  
Rabies Virus ◽  
Ebola Virus ◽  
Animal Health ◽  
Nipah Virus ◽  
Emerging Infectious Diseases ◽  
Hendra Virus ◽  
Marburg Virus ◽  
Associated Diseases ◽  
Zoonotic Viruses

Emerging infectious diseases pose a significant threat to human and animal health. Increasingly, emerging and re-emerging infectious diseases are of zoonotic origin and are derived from wildlife. Bats have been identified as an important reservoir of zoonotic viruses belonging to a range of different virus families including SARSCoronavirus, Rabies virus, Hendra virus, Nipah virus, Marburg virus and Ebola virus.

scholarly journals Brief review on remdesivir

2021 ◽  
pp. 57
Author(s):  
Venkata Niharika Daka ◽  
Lakshmi Sravanthi Bandi ◽  
Sushma Alla ◽  
Venkata Spandana Cheedella ◽  
Sadasiva Rao Galaba
Keyword(s):  
Ebola Virus ◽  
Nipah Virus ◽  
Antiviral Drug ◽  
Hendra Virus ◽  
Marburg Virus ◽  
Nucleoside Triphosphate ◽  
Syncytial Virus ◽  
Respiratory Epithelial

Remdesivir is an investigational broad-spectrum small-molecule antiviral drug that has confirmed interest in the direction of RNA viruses in numerous families, which encompass Coronaviridae (alongside aspect SARS-CoV, MERS-CoV, and lines of bat coronaviruses able to infecting human respiratory epithelial cells), Paramyxoviridae (alongside aspect Nipah virus, respiratory syncytial virus, and Hendra virus), and Filoviridae (alongside aspect Ebola virus). Originally superior to cope with Ebola virus infection , remdesivir is a prodrug of the determine adenosine analog, each of which can be metabolized into an energetic nucleoside triphosphate (NTP) via the host. The determine nucleoside, GS-441524, has displayed antiviral interest within the direction of SARS-CoV, Marburg virus , and pussycat infectious peritonitis virus, amongst others. A fashion of research have tested the effects of these pills on coronaviruses (CoVs) each in vitro and in vivo the use of mouse and non-human primate animal models.

scholarly journals Novel Functions of Hendra Virus G N-Glycans and Comparisons to Nipah Virus

2015 ◽  
Vol 89 (14) ◽  
pp. 7235-7247 ◽  
Author(s):  
Birgit G. Bradel-Tretheway ◽  
Qian Liu ◽  
Jacquelyn A. Stone ◽  
Samantha McInally ◽  
Hector C. Aguilar
Keyword(s):  
Membrane Fusion ◽  
Cell Fusion ◽  
Immune Evasion ◽  
Viral Entry ◽  
Nipah Virus ◽  
Hendra Virus ◽  
Viral Attachment ◽  
Glycoprotein G ◽  
Protein Functions ◽  
Cell Cell

ABSTRACTHendra virus (HeV) and Nipah virus (NiV) are reportedly the most deadly pathogens within theParamyxoviridaefamily. These two viruses bind the cellular entry receptors ephrin B2 and/or ephrin B3 via the viral attachment glycoprotein G, and the concerted efforts of G and the viral fusion glycoprotein F result in membrane fusion. Membrane fusion is essential for viral entry into host cells and for cell-cell fusion, a hallmark of the disease pathobiology. HeV G is heavily N-glycosylated, but the functions of the N-glycans remain unknown. We disrupted eight predicted N-glycosylation sites in HeV G by conservative mutations (Asn to Gln) and found that six out of eight sites were actually glycosylated (G2 to G7); one in the stalk (G2) and five in the globular head domain (G3 to G7). We then tested the roles of individual and combined HeV G N-glycan mutants and found functions in the modulation of shielding against neutralizing antibodies, intracellular transport, G-F interactions, cell-cell fusion, and viral entry. Between the highly conserved HeV and NiV G glycoproteins, similar trends in the effects of N-glycans on protein functions were observed, with differences in the levels at which some N-glycan mutants affected such functions. While the N-glycan in the stalk domain (G2) had roles that were highly conserved between HeV and NiV G, individual N-glycans in the head affected the levels of several protein functions differently. Our findings are discussed in the context of their contributions to our understanding of HeV and NiV pathogenesis and immune responses.IMPORTANCEViral envelope glycoproteins are important for viral pathogenicity and immune evasion. N-glycan shielding is one mechanism by which immune evasion can be achieved. In paramyxoviruses, viral attachment and membrane fusion are governed by the close interaction of the attachment proteins H/HN/G and the fusion protein F. In this study, we show that the attachment glycoprotein G of Hendra virus (HeV), a deadly paramyxovirus, is N-glycosylated at six sites (G2 to G7) and that most of these sites have important roles in viral entry, cell-cell fusion, G-F interactions, G oligomerization, and immune evasion. Overall, we found that the N-glycan in the stalk domain (G2) had roles that were very conserved between HeV G and the closely related Nipah virus G, whereas individual N-glycans in the head quantitatively modulated several protein functions differently between the two viruses.

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