scholarly journals Inactivated Recombinant Rabies Viruses Displaying Canine Distemper Virus Glycoproteins Induce Protective Immunity against Both Pathogens

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Renata da Fontoura Budaszewski ◽  
Andrew Hudacek ◽  
Bevan Sawatsky ◽  
Beate Krämer ◽  
Xiangping Yin ◽  
...  
Keyword(s):  
Immune Responses ◽  
Fusion Protein ◽  
Rabies Virus ◽  
Canine Distemper Virus ◽  
Canine Distemper ◽  
Wild Type ◽  
Attachment Protein ◽  
Recombinant Viruses ◽  
Virus Particles ◽  
Residual Virulence

ABSTRACT The development of multivalent vaccines is an attractive methodology for the simultaneous prevention of several infectious diseases in vulnerable populations. Both canine distemper virus (CDV) and rabies virus (RABV) cause lethal disease in wild and domestic carnivores. While RABV vaccines are inactivated, the live-attenuated CDV vaccines retain residual virulence for highly susceptible wildlife species. In this study, we developed recombinant bivalent vaccine candidates based on recombinant vaccine strain rabies virus particles, which concurrently display the protective CDV and RABV glycoprotein antigens. The recombinant viruses replicated to near-wild-type titers, and the heterologous glycoproteins were efficiently expressed and incorporated in the viral particles. Immunization of ferrets with beta-propiolactone-inactivated recombinant virus particles elicited protective RABV antibody titers, and animals immunized with a combination of CDV attachment protein- and fusion protein-expressing recombinant viruses were protected from lethal CDV challenge. However, animals that were immunized with only a RABV expressing the attachment protein of CDV vaccine strain Onderstepoort succumbed to infection with a more recent wild-type strain, indicating that immune responses to the more conserved fusion protein contribute to protection against heterologous CDV strains. IMPORTANCE Rabies virus and canine distemper virus (CDV) cause high mortality rates and death in many carnivores. While rabies vaccines are inactivated and thus have an excellent safety profile and high stability, live-attenuated CDV vaccines can retain residual virulence in highly susceptible species. Here we generated recombinant inactivated rabies viruses that carry one of the CDV glycoproteins on their surface. Ferrets immunized twice with a mix of recombinant rabies viruses carrying the CDV fusion and attachment glycoproteins were protected from lethal CDV challenge, whereas all animals that received recombinant rabies viruses carrying only the CDV attachment protein according to the same immunization scheme died. Irrespective of the CDV antigens used, all animals developed protective titers against rabies virus, illustrating that a bivalent rabies virus-based vaccine against CDV induces protective immune responses against both pathogens.

scholarly journals Sequence Analysis and Expression of the Attachment and Fusion Proteins of Canine Distemper Virus Wild-Type Strain A75/17

1999 ◽  
Vol 73 (3) ◽  
pp. 2263-2269 ◽  
Author(s):  
Pascal Cherpillod ◽  
Karin Beck ◽  
Andreas Zurbriggen ◽  
Riccardo Wittek
Keyword(s):  
Amino Acid ◽  
Fusion Protein ◽  
Translation Initiation ◽  
Fusion Proteins ◽  
Canine Distemper Virus ◽  
Protein A ◽  
Biological Properties ◽  
Canine Distemper ◽  
Wild Type ◽  
Attachment Protein

ABSTRACT The biological properties of wild-type A75/17 and cell culture-adapted Onderstepoort canine distemper virus differ markedly. To learn more about the molecular basis for these differences, we have isolated and sequenced the protein-coding regions of the attachment and fusion proteins of wild-type canine distemper virus strain A75/17. In the attachment protein, a total of 57 amino acid differences were observed between the Onderstepoort strain and strain A75/17, and these were distributed evenly over the entire protein. Interestingly, the attachment protein of strain A75/17 contained an extension of three amino acids at the C terminus. Expression studies showed that the attachment protein of strain A75/17 had a higher apparent molecular mass than the attachment protein of the Onderstepoort strain, in both the presence and absence of tunicamycin. In the fusion protein, 60 amino acid differences were observed between the two strains, of which 44 were clustered in the much smaller F2 portion of the molecule. Significantly, the AUG that has been proposed as a translation initiation codon in the Onderstepoort strain is an AUA codon in strain A75/17. Detailed mutation analyses showed that both the first and second AUGs of strain A75/17 are the major translation initiation sites of the fusion protein. Similar analyses demonstrated that, also in the Onderstepoort strain, the first two AUGs are the translation initiation codons which contribute most to the generation of precursor molecules yielding the mature form of the fusion protein.

scholarly journals The fusion protein of wild-type canine distemper virus is a major determinant of persistent infection

Virology ◽  
2005 ◽  
Vol 337 (2) ◽  
pp. 312-326 ◽  
Author(s):  
Philippe Plattet ◽  
Jean-Paul Rivals ◽  
Benoît Zuber ◽  
Jean-Marc Brunner ◽  
Andreas Zurbriggen ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Persistent Infection ◽  
Canine Distemper Virus ◽  
Major Determinant ◽  
Canine Distemper ◽  
Wild Type

scholarly journals Identification of Amino Acid Substitutions with Compensational Effects in the Attachment Protein of Canine Distemper Virus

2014 ◽  
Vol 88 (14) ◽  
pp. 8057-8064 ◽  
Author(s):  
Ursula Sattler ◽  
Mojtaba Khosravi ◽  
Mislay Avila ◽  
Paola Pilo ◽  
Johannes P. Langedijk ◽  
...  
Keyword(s):  
Amino Acid ◽  
Single Nucleotide Polymorphisms ◽  
Canine Distemper Virus ◽  
Nucleotide Polymorphisms ◽  
Canine Distemper ◽  
Wild Type ◽  
Attachment Protein ◽  
Single Nucleotide ◽  
Hemagglutinin Gene ◽  
H Gene

ABSTRACTThe hemagglutinin (H) gene of canine distemper virus (CDV) encodes the receptor-binding protein. This protein, together with the fusion (F) protein, is pivotal for infectivity since it contributes to the fusion of the viral envelope with the host cell membrane. Of the two receptors currently known for CDV (nectin-4 and the signaling lymphocyte activation molecule [SLAM]), SLAM is considered the most relevant for host susceptibility. To investigate how evolution might have impacted the host-CDV interaction, we examined the functional properties of a series of missense single nucleotide polymorphisms (SNPs) naturally accumulating within the H-gene sequences during the transition between two distinct but related strains. The two strains, a wild-type strain and a consensus strain, were part of a single continental outbreak in European wildlife and occurred in distinct geographical areas 2 years apart. The deduced amino acid sequence of the two H genes differed at 5 residues. A panel of mutants carrying all the combinations of the SNPs was obtained by site-directed mutagenesis. The selected mutant, wild type, and consensus H proteins were functionally evaluated according to their surface expression, SLAM binding, fusion protein interaction, and cell fusion efficiencies. The results highlight that the most detrimental functional effects are associated with specific sets of SNPs. Strikingly, an efficient compensational system driven by additional SNPs appears to come into play, virtually neutralizing the negative functional effects. This system seems to contribute to the maintenance of the tightly regulated function of the H-gene-encoded attachment protein.IMPORTANCETo investigate how evolution might have impacted the host-canine distemper virus (CDV) interaction, we examined the functional properties of naturally occurring single nucleotide polymorphisms (SNPs) in the hemagglutinin gene of two related but distinct strains of CDV. The hemagglutinin gene encodes the attachment protein, which is pivotal for infection. Our results show that few SNPs have a relevant detrimental impact and they generally appear in specific combinations (molecular signatures). These drastic negative changes are neutralized by compensatory mutations, which contribute to maintenance of an overall constant bioactivity of the attachment protein. This compensational mechanism might reflect the reaction of the CDV machinery to the changes occurring in the virus following antigenic variations critical for virulence.

A recombinant canine distemper virus expressing a modified rabies virus glycoprotein induces immune responses in mice

Virus Genes ◽  
2015 ◽  
Vol 50 (3) ◽  
pp. 434-441 ◽  
Author(s):  
Zhili Li ◽  
Jigui Wang ◽  
Daoli Yuan ◽  
Shuang Wang ◽  
Jiazeng Sun ◽  
...  
Keyword(s):  
Immune Responses ◽  
Rabies Virus ◽  
Canine Distemper Virus ◽  
Canine Distemper ◽  
Rabies Virus Glycoprotein ◽  
Virus Glycoprotein

Humoral and cell-mediated immune responses in DNA immunized mink challenged with wild-type canine distemper virus

Vaccine ◽  
2009 ◽  
Vol 27 (35) ◽  
pp. 4791-4797 ◽  
Author(s):  
Line Nielsen ◽  
Mette Søgaard ◽  
Peter Karlskov-Mortensen ◽  
Trine Hammer Jensen ◽  
Tove Dannemann Jensen ◽  
...  
Keyword(s):  
Immune Responses ◽  
Canine Distemper Virus ◽  
Canine Distemper ◽  
Wild Type

TLR4 regulates rabies virus-induced humoral immunity through recruitment of cDC2 to lymph organs

2021 ◽  
Author(s):  
Chen Chen ◽  
Chengguang Zhang ◽  
Haoqi Li ◽  
Zongmei Wang ◽  
Yueming Yuan ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Rabies Virus ◽  
Humoral Immunity ◽  
Humoral Immune Response ◽  
Critical Role ◽  
Wild Type ◽  
Humoral Immune ◽  
Specific Igg ◽  
Molecular Patterns

Rabies, caused by rabies virus (RABV), is fatal to both humans and animals around the world. Effective clinical therapy for rabies has not been achieved, and vaccination is the most effective means of preventing and controlling rabies. Although different vaccines, such as live attenuated and inactivated vaccines, can induce different immune responses, different expression of pattern recognition receptors (PRRs) also causes diverse immune responses. Toll-like receptor 4 (TLR4) is a pivotal PRR that induces cytokine production and bridges innate and adaptive immunity. Importantly, TLR4 recognizes various virus-derived pathogen-associated molecular patterns (PAMPs) and virus-induced damage-associated molecular patterns (DAMPs), usually leading to the activation of immune cells. However, the role of TLR4 in the humoral immune response induced by RABV has not been revealed yet. Based on TLR4-deficient ( TLR4 -/- ) and wild-type (WT) mouse models, we report that TLR4-dependent recruitment of the conventional type-2 dendritic cells (CD8α - CD11b + cDC2) into secondary lymph organs (SLOs) is critical for antigen presentation. cDC2-initiated differentiation of Tfh cells promotes the proliferation of germinal centre (GC) B cells, the formation of GCs, and the production of plasma cells (PCs), all of which contribute to the production of RABV-specific IgG and virus-neutralizing antibodies (VNAs). Collectively, our work demonstrates that TLR4 is necessary for the recruitment of cDC2 and for the induction of RABV-induced humoral immunity, which is regulated by the cDC2-Tfh-GC B axis. IMPORTANCE Vaccination is the most efficient method to prevent rabies. TLR4, a well-known immune sensor, plays a critical role in initiating innate immune response. Here, we found that TLR4 deficiency ( TLR4 -/- ) mice suppressed the induction of humoral immune response after immunization with rabies virus (RABV), including reduced production of VNAs and RABV-specific IgG, compared with that occurred in wild-type (WT) mice. As a consequence, TLR4 -/- mice exhibited higher mortality than WT mice after challenge with virulent RABV. Importantly, further investigation found that TLR4 signaling promoted the recruitment of cDC2 (CD8α + CD11b - ), a subset of cDCs known to induce CD4 + T cell immunity through their MHC-II presentation machinery. Our results imply that TLR4 is indispensable for an efficient humoral response to rabies vaccine, which provides new insight into the development of novel rabies vaccines.

scholarly journals Molecular detection and phylogenetic relationship of wild-type strains of canine distemper virus in symptomatic dogs from Uberlândia, Minas Gerais

2015 ◽  
Vol 67 (6) ◽  
pp. 1510-1518
Author(s):  
S.A. Headley ◽  
T.R. Santos ◽  
L. Bodnar ◽  
J.P.E. Saut ◽  
A.P. Silva ◽  
...  
Keyword(s):  
Canine Distemper Virus ◽  
Phylogenetic Analyses ◽  
Clinical Manifestations ◽  
N Gene ◽  
Clinical Samples ◽  
Canine Distemper ◽  
Wild Type ◽  
Age Related ◽  
Relationship Of ◽  
Type Strains

This study investigated the occurrence of canine distemper virus (CDV) by evaluating the presence of viral RNA within urine samples of dogs from Uberlândia, MG, with clinical manifestations suggestive of infection by CDV by targeting the CDV N gene. Of the clinical samples collected ( n =33), CDV viruria was detected in 45.5%. Five dogs died spontaneously; all had characteristic CDV-associated histopathological alterations and demonstrated CDV viruria. Statistical analyses revealed that the age, gender, breed, or the organ system of the dog affected had no influence on the occurrence of canine distemper. Myoclonus and motor incoordination were the most significant neurological manifestations observed. A direct association was observed between keratoconjunctivitis and dogs with CDV viruria. These findings suggest that CDV viruria in symptomatic dogs might not be age related, and that symptomatic dogs can demonstrate clinical manifestations attributed to CDV without viruria identified by RT-PCR. Additionally, the results of the sequence identities analysed have suggested that all Brazilian wild-type strains of CDV currently identified are closely related and probably originated from the same lineage of CDV. Nevertheless, phylogenetic analyses suggest that there are different clusters of wild-type strains of CDV circulating within urban canine populations in Brazil.

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 Canine Distemper Virus Fusion Activation: Critical Role of Residue E123 of CD150/SLAM

2015 ◽  
Vol 90 (3) ◽  
pp. 1622-1637 ◽  
Author(s):  
Mojtaba Khosravi ◽  
Fanny Bringolf ◽  
Silvan Röthlisberger ◽  
Maria Bieringer ◽  
Jürgen Schneider-Schaulies ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Binding Site ◽  
Measles Virus ◽  
Canine Distemper Virus ◽  
Cell Entry ◽  
Physical Interaction ◽  
Canine Distemper ◽  
Attachment Protein ◽  
Binding Interfaces

ABSTRACTMeasles virus (MeV) and canine distemper virus (CDV) possess tetrameric attachment proteins (H) and trimeric fusion proteins, which cooperate with either SLAM or nectin 4 receptors to trigger membrane fusion for cell entry. While the MeV H-SLAM cocrystal structure revealed the binding interface, two distinct oligomeric H assemblies were also determined. In one of the conformations, two SLAM units were sandwiched between two discrete H head domains, thus spotlighting two binding interfaces (“front” and “back”). Here, we investigated the functional relevance of both interfaces in activating the CDV membrane fusion machinery. While alanine-scanning mutagenesis identified five critical regulatory residues in the front H-binding site of SLAM, the replacement of a conserved glutamate residue (E at position 123, replaced with A [E123A]) led to the most pronounced impact on fusion promotion. Intriguingly, while determination of the interaction of H with the receptor using soluble constructs revealed reduced binding for the identified SLAM mutants, no effect was recorded when physical interaction was investigated with the full-length counterparts of both molecules. Conversely, although mutagenesis of three strategically selected residues within the back H-binding site of SLAM did not substantially affect fusion triggering, nevertheless, the mutants weakened the H-SLAM interaction recorded with the membrane-anchored protein constructs. Collectively, our findings support a mode of binding between the attachment protein and the V domain of SLAM that is common to all morbilliviruses and suggest a major role of the SLAM residue E123, located at the front H-binding site, in triggering the fusion machinery. However, our data additionally support the hypothesis that other microdomain(s) of both glycoproteins (including the back H-binding site) might be required to achieve fully productive H-SLAM interactions.IMPORTANCEA complete understanding of the measles virus and canine distemper virus (CDV) cell entry molecular framework is still lacking, thus impeding the rational design of antivirals. Both viruses share many biological features that partially rely on the use of analogous Ig-like host cell receptors, namely, SLAM and nectin 4, for entering immune and epithelial cells, respectively. Here, we provide evidence that the mode of binding between the membrane-distal V domain of SLAM and the attachment protein (H) of morbilliviruses is very likely conserved. Moreover, although structural information revealed two discrete conformational states of H, one of the structures displayed two H-SLAM binding interfaces (“front” and “back”). Our data not only spotlight the front H-binding site of SLAM as the main determinant of membrane fusion promotion but suggest that the triggering efficiency of the viral entry machinery may rely on a local conformational change within the front H-SLAM interactive site rather than the binding affinity.

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