scholarly journals Computational Analysis Reveals a Critical Point Mutation in the N-Terminal Region of the Signaling Lymphocytic Activation Molecule Responsible for the Cross-Species Infection with Canine Distemper Virus

2021 ◽  
Author(s):  
Yuta Yamamoto ◽  
Shogo Nakano ◽  
Fumio Seki ◽  
Yasuteru Shigeta ◽  
Sohei Ito ◽  
...  
Keyword(s):  
Computational Chemistry ◽  
Measles Virus ◽  
Canine Distemper Virus ◽  
Infection Process ◽  
Terminal Region ◽  
Canine Distemper ◽  
Signaling Lymphocytic Activation Molecule ◽  
High Flexibility ◽  
H Protein

Infection of hosts by morbilliviruses is facilitated by the interaction between viral hemagglutinin (H-protein) and the signaling lymphocytic activation molecule (SLAM). Recently, the functional importance of the N-terminal region of human SLAM as a measles virus receptor was demonstrated. However, the functional roles of this region in the infection process by other morbilliviruses and host range determination remain unknown partly because this region is highly flexible, which has hampered accurate structure determination of this region by X-ray crystallography. In this study, we analyzed the interaction between the H-protein from canine distemper virus (CDV-H) and SLAMs by a computational chemistry approach. Molecular dynamics simulations and fragment molecular orbital analysis demonstrated that the unique His28 in the N-terminal region of SLAM from Macaca is a key determinant that enables formation of a stable interaction with CDV-H, providing a basis for CDV infection in Macaca. The computational chemistry approach presented should enable determination of molecular interactions involving regions of proteins that are difficult to predict from crystal structures because of their high flexibility.

scholarly journals Computational Analysis Reveals a Critical Point Mutation in the N-Terminal Region of the Signaling Lymphocytic Activation Molecule Responsible for the Cross-Species Infection with Canine Distemper Virus

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1262
Author(s):  
Yuta Yamamoto ◽  
Shogo Nakano ◽  
Fumio Seki ◽  
Yasuteru Shigeta ◽  
Sohei Ito ◽  
...  
Keyword(s):  
Computational Chemistry ◽  
Measles Virus ◽  
Canine Distemper Virus ◽  
Infection Process ◽  
Terminal Region ◽  
Canine Distemper ◽  
Signaling Lymphocytic Activation Molecule ◽  
High Flexibility ◽  
H Protein

Infection of hosts by morbilliviruses is facilitated by the interaction between viral hemagglutinin (H-protein) and the signaling lymphocytic activation molecule (SLAM). Recently, the functional importance of the n-terminal region of human SLAM as a measles virus receptor was demonstrated. However, the functional roles of this region in the infection process by other morbilliviruses and host range determination remain unknown, partly because this region is highly flexible, which has hampered accurate structure determination of this region by X-ray crystallography. In this study, we analyzed the interaction between the H-protein from canine distemper virus (CDV-H) and SLAMs by a computational chemistry approach. Molecular dynamics simulations and fragment molecular orbital analysis demonstrated that the unique His28 in the N-terminal region of SLAM from Macaca is a key determinant that enables the formation of a stable interaction with CDV-H, providing a basis for CDV infection in Macaca. The computational chemistry approach presented should enable the determination of molecular interactions involving regions of proteins that are difficult to predict from crystal structures because of their high flexibility.

scholarly journals The Hemagglutinin of Canine Distemper Virus Determines Tropism and Cytopathogenicity

2001 ◽  
Vol 75 (14) ◽  
pp. 6418-6427 ◽  
Author(s):  
Veronika von Messling ◽  
Gert Zimmer ◽  
Georg Herrler ◽  
Ludwig Haas ◽  
Roberto Cattaneo
Keyword(s):  
Vaccine Strain ◽  
Measles Virus ◽  
Canine Distemper Virus ◽  
Syncytium Formation ◽  
Genetic System ◽  
Reverse Genetic System ◽  
Canine Distemper ◽  
Large Plaque ◽  
Recombinant Viruses ◽  
H Protein

ABSTRACT Canine distemper virus (CDV) and measles virus (MV) cause severe illnesses in their respective hosts. The viruses display a characteristic cytopathic effect by forming syncytia in susceptible cells. For CDV, the proficiency of syncytium formation varies among different strains and correlates with the degree of viral attenuation. In this study, we examined the determinants for the differential fusogenicity of the wild-type CDV isolate 5804Han89 (CDV5804), the small- and large-plaque-forming variants of the CDV vaccine strain Onderstepoort (CDVOS and CDVOL, respectively), and the MV vaccine strain Edmonston B (MVEdm). The cotransfection of different combinations of fusion (F) and hemagglutinin (H) genes in Vero cells indicated that the H protein is the main determinant of fusion efficiency. To verify the significance of this observation in the viral context, a reverse genetic system to generate recombinant CDVs was established. This system is based on a plasmid containing the full-length antigenomic sequence of CDVOS. The coding regions of the H proteins of all CDV strains and MVEdm were introduced into the CDV and MV genetic backgrounds, and recombinant viruses rCDV-H5804, rCDV-HOL, rCDV-HEdm, rMV-H5804, rMV-HOL, and rMV-HOS were recovered. Thus, the H proteins of the two morbilliviruses are interchangeable and fully functional in a heterologous complex. This is in contrast with the glycoproteins of other members of the familyParamyxoviridae, which do not function efficiently with heterologous partners. The fusogenicity, growth characteristics, and tropism of the recombinant viruses were examined and compared with those of the parental strains. All these characteristics were found to be predominantly mediated by the H protein regardless of the viral backbone used.

scholarly journals Canine Distemper Virus Spread and Transmission to Naive Ferrets: Selective Pressure on Signaling Lymphocyte Activation Molecule-Dependent Entry

2018 ◽  
Vol 92 (15) ◽  
Author(s):  
Bevan Sawatsky ◽  
Roberto Cattaneo ◽  
Veronika von Messling
Keyword(s):  
Protein Interactions ◽  
Measles Virus ◽  
Canine Distemper Virus ◽  
Lymphocyte Activation ◽  
Canine Distemper ◽  
Attachment Protein ◽  
Binding Surface ◽  
Contact Transmission ◽  
Compensatory Mutations ◽  
H Protein

ABSTRACTUpon infection, morbilliviruses such as measles virus, rinderpest virus, and canine distemper virus (CDV) initially target immune cells via the signaling lymphocyte activation molecule (SLAM) before spreading to respiratory epithelia through the adherens junction protein nectin-4. However, the roles of these receptors in transmission from infected to naive hosts have not yet been formally tested. To experimentally addressing this question, we established a model of CDV contact transmission between ferrets. We show here that transmission of wild-type CDV sometimes precedes the onset of clinical disease. In contrast, transmission was not observed in most animals infected with SLAM- or nectin-4-blind CDVs, even though all animals infected with the nectin-4-blind virus developed sustained viremia. There was an unexpected case of transmission of a nectin-4-blind virus, possibly due to biting. Another unprecedented event was transient viremia in an infection with a SLAM-blind virus. We identified three compensatory mutations within or near the SLAM-binding surface of the attachment protein. A recombinant CDV expressing the mutated attachment protein regained the ability to infect ferret lymphocytesin vitro, but its replication was not as efficient as that of wild-type CDV. Ferrets infected with this virus developed transient viremia and fever, but there was no transmission to naive contacts. Our study supports the importance of epithelial cell infection and of sequential CDV H protein interactions first with SLAM and then nectin-4 receptors for transmission to naive hosts. It also highlights thein vivoselection pressure on the H protein interactions with SLAM.IMPORTANCEMorbilliviruses such as measles virus, rinderpest virus, and canine distemper virus (CDV) are highly contagious. Despite extensive knowledge of how morbilliviruses interact with their receptors, little is known about how those interactions influence viral transmission to naive hosts. In a ferret model of CDV contact transmission, we showed that sequential use of the signaling lymphocytic activation molecule (SLAM) and nectin-4 receptors is essential for transmission. In one animal infected with a SLAM-blind CDV, we documented mild viremia due to the acquisition of three compensatory mutations within or near the SLAM-binding surface. The interaction, however, was not sufficient to cause disease or sustain transmission to naive contacts. This work confirms the sequential roles of SLAM and nectin-4 in morbillivirus transmission and highlights the selective pressure directed toward productive interactions with SLAM.

scholarly journals CD9-dependent regulation of Canine distemper virus-induced cell–cell fusion segregates with the extracellular domain of the haemagglutinin

2006 ◽  
Vol 87 (6) ◽  
pp. 1635-1642 ◽  
Author(s):  
K. Singethan ◽  
E. Topfstedt ◽  
S. Schubert ◽  
W. P. Duprex ◽  
B. K. Rima ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Measles Virus ◽  
Canine Distemper Virus ◽  
Transmembrane Protein ◽  
Extracellular Domain ◽  
Canine Distemper ◽  
Viral Glycoprotein ◽  
F Protein ◽  
H Protein ◽  
Cell Cell

Antibodies to CD9, a member of the tetraspan transmembrane-protein family, selectively inhibit Canine distemper virus (CDV)-induced cell–cell fusion. Neither CDV-induced virus–cell fusion nor cell–cell fusion induced by the closely related morbillivirus Measles virus (MV) is affected by anti-CD9 antibodies. As CDV does not bind CD9, an unknown, indirect mechanism is responsible for the observed inhibition of cell–cell fusion. It was investigated whether this effect was restricted to only one viral glycoprotein, either the haemagglutinin (H) or the fusion (F) protein, which form a fusion complex on the surface of virions and infected cells, or whether it is dependent on both in transient co-transfection assays. The susceptibility to CD9 antibodies segregates with the H protein of CDV. By exchanging portions of the H proteins of CDV and MV, it was determined that the complete extracellular domain, including the predicted stem structure (stem 1, barrel strand 1 and stem 2) and globular head domain, of the CDV-H protein mediates the effect. This suggests that interaction of the CDV-H protein with an unknown cellular receptor(s) is regulated by CD9, rather than F protein-mediated membrane fusion.

scholarly journals Nearby Clusters of Hemagglutinin Residues Sustain SLAM-Dependent Canine Distemper Virus Entry in Peripheral Blood Mononuclear Cells

2005 ◽  
Vol 79 (9) ◽  
pp. 5857-5862 ◽  
Author(s):  
Veronika von Messling ◽  
Numan Oezguen ◽  
Qi Zheng ◽  
Sompong Vongpunsawad ◽  
Werner Braun ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Measles Virus ◽  
Canine Distemper Virus ◽  
Structural Model ◽  
Mononuclear Cells ◽  
Canine Distemper ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Signaling Lymphocytic Activation Molecule

ABSTRACT Signaling lymphocytic activation molecule (SLAM, CD150) is the universal morbillivirus receptor. Based on the identification of measles virus (MV) hemagglutinin (H) amino acids supporting human SLAM-dependent cell entry, we mutated canine distemper virus (CDV) H and identified residues necessary for efficient canine SLAM-dependent membrane fusion. These residues are located in two nearby clusters in a new CDV H structural model. To completely abolish SLAM-dependent fusion, combinations of mutations were necessary. We rescued a SLAM-blind recombinant CDV with six mutations that did not infect ferret peripheral blood mononuclear cells while retaining full infectivity in epithelial cells.

scholarly journals Antiviral Screen against Canine Distemper Virus-Induced Membrane Fusion Activity

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 128
Author(s):  
Neeta Shrestha ◽  
Flavio M. Gall ◽  
Jonathan Vesin ◽  
Marc Chambon ◽  
Gerardo Turcatti ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Measles Virus ◽  
Canine Distemper Virus ◽  
Rna Virus ◽  
Preventive Measure ◽  
Close Relative ◽  
Fusion Activity ◽  
Canine Distemper

Canine distemper virus (CDV), a close relative of the human pathogen measles virus (MeV), is an enveloped, negative sense RNA virus that belongs to the genus Morbillivirus and causes severe diseases in dogs and other carnivores. Although the vaccination is available as a preventive measure against the disease, the occasional vaccination failure highlights the importance of therapeutic alternatives such as antivirals against CDV. The morbilliviral cell entry system relies on two interacting envelope glycoproteins: the attachment (H) and fusion (F) proteins. Here, to potentially discover novel entry inhibitors targeting CDV H, F and/or the cognate receptor: signaling lymphocyte activation molecule (SLAM) proteins, we designed a quantitative cell-based fusion assay that matched high-throughput screening (HTS) settings. By screening two libraries of small molecule compounds, we successfully identified two membrane fusion inhibitors (F2736-3056 and F2261-0043). Although both inhibitors exhibited similarities in structure and potency with the small molecule compound 3G (an AS-48 class morbilliviral F-protein inhibitor), F2736-3056 displayed improved efficacy in blocking fusion activity when a 3G-escape variant was employed. Altogether, we present a cell-based fusion assay that can be utilized not only to discover antiviral agents against CDV but also to dissect the mechanism of morbilliviral-mediated cell-binding and cell-to-cell fusion activity.

scholarly journals Genetic diversity of the attachment (H) protein gene of current field isolates of canine distemper virus.

1997 ◽  
Vol 78 (2) ◽  
pp. 367-372 ◽  
Author(s):  
G Bolt ◽  
P Arctander ◽  
T D Jensen ◽  
M J Appel ◽  
E Gottschalck ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Canine Distemper Virus ◽  
Protein Gene ◽  
Canine Distemper ◽  
Current Field ◽  
Field Isolates ◽  
H Protein

scholarly journals Disease Duration Determines Canine Distemper Virus Neurovirulence

2007 ◽  
Vol 81 (21) ◽  
pp. 12066-12070 ◽  
Author(s):  
François Bonami ◽  
Penny A. Rudd ◽  
Veronika von Messling
Keyword(s):  
Canine Distemper Virus ◽  
Disease Duration ◽  
Subsequent Development ◽  
Neurological Involvement ◽  
Disease Course ◽  
Canine Distemper ◽  
Wild Type ◽  
Neurological Signs ◽  
H Protein ◽  
Type Strains

ABSTRACT The Morbillivirus hemagglutinin (H) protein mediates attachment to the target cell. To evaluate its contribution to canine distemper virus neurovirulence, we exchanged the H proteins of the wild-type strains 5804P and A75 and assessed the pathogenesis of the chimeric viruses in ferrets. Both strains are lethal to ferrets; however, 5804P causes a 2-week disease without neurological signs, whereas A75 is associated with a longer disease course and neurological involvement. We observed that both H proteins supported neuroinvasion and the subsequent development of clinical neurological signs if given enough time, demonstrating that disease duration is the main neurovirulence determinant.

scholarly journals Protective Immunity against Canine Distemper Virus in Dogs Induced by Intranasal Immunization with a Recombinant Probiotic Expressing the Viral H Protein

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 213
Author(s):  
Yanping Jiang ◽  
Shuo Jia ◽  
Dianzhong Zheng ◽  
Fengsai Li ◽  
Shengwen Wang ◽  
...  
Keyword(s):  
Canine Distemper Virus ◽  
Immunoglobulin A ◽  
Canine Distemper ◽  
Intranasal Route ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Protection Efficacy ◽  
Specific Igg ◽  
High Level ◽  
H Protein

Canine distemper virus (CDV) elicits a severe contagious disease in a broad range of hosts. CDV mortality rates are 50% in domestic dogs and 100% in ferrets. Its primary infection sites are respiratory and intestinal mucosa. This study aimed to develop an effective mucosal CDV vaccine using a non-antibiotic marked probiotic pPGΔCm-T7g10-EGFP-H/L. casei 393 strain expressing the CDV H protein. Its immunogenicity in BALB/c mice was evaluated using intranasal and oral vaccinations, whereas in dogs the intranasal route was used for vaccination. Our results indicate that this probiotic vaccine can stimulate a high level of secretory immunoglobulin A (sIgA)-based mucosal and IgG-based humoral immune responses in mice. SIgA levels in the nasal lavage and lungs were significantly higher in intranasally vaccinated mice than those in orally vaccinated mice. Both antigen-specific IgG and sIgA antibodies were effectively elicited in dogs through the intranasal route and demonstrated superior immunogenicity. The immune protection efficacy of the probiotic vaccine was evaluated by challenging the immunized dogs with virulent CDV 42 days after primary immunization. Dogs of the pPGΔCm-T7g10-EGFP-H/L. casei 393 group were completely protected against CDV. The proposed probiotic vaccine could be promising for protection against CDV infection in dogs.

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