Tropism and molecular pathogenesis of canine distemper virus

Abstract

Background: Canine distemper virus (CDV), currently termed Canine morbillivirus, is an extremely contagious disease that affects dogs. It is identified as a multiple cell tropism pathogen, and its host range includes a vast array of species. As a member of Mononegavirales, CDV has a negative, single-stranded RNA genome, which encodes eight proteins.

Main body: Regarding the molecular pathogenesis, the hemagglutinin protein (H) plays a crucial role both in the antigenic recognition and the viral interaction with SLAM and nectin-4, the host cells' receptors. These cellular receptors have been studied widely as CDV receptors in vitro in different cellular models. The SLAM receptor is located in lymphoid cells; therefore, the infection of these cells by CDV leads to immunosuppression, the severity of which can lead to variability in the clinical disease with the potential of secondary bacterial infection, up to and including the development of neurological signs in its later stage.

Conclusion: Improving the understanding of the CDV molecules implicated in the determination of infection, especially the H protein, can help to enhance the biochemical comprehension of the difference between a wide range of CDV variants, their tropism, and different steps in viral infection. The regions of interaction between the viral proteins and the identified host cell receptors have been elucidated to facilitate this understanding. Hence, this review describes the significant molecular and cellular characteristics of CDV that contribute to viral pathogenesis.

Keywords: Canine distemper virus; Canine morbillivirus; Molecular pathogenesis; Neuropathogenesis; Tropism; Zoonosis.

Fig. 1

CDV virion and genome organization. a Schematic diagrams of CDV particle in cross-section N: nucleocapsid, P: phosphoprotein, M: matrix protein, F: fusion protein, H: hemagglutinin, L: large polymerase protein. b Map of genomic RNA (3′ to 5′) of CDV. Each box represents a separately encoded mRNA; multiple distinct ORFs within a single mRNA are indicated in overlapping boxes on P

Fig. 2

Phylogenetic tree constructed from the alignment of complete H gene sequences obtained from GenBank, which represents all current CDV-described genotypes. 67 H sequences representing all genotypes were retrieved and aligned with ClustalW using MEGA 6 software. MEGA6.0 was also used for phylogeny inference according to the Maximum Likelihood algorithm method based on the Tamura 3-parameter model. The rate variation among sites was modeled using a gamma distribution (shape parameter = 5). The robustness of the hypothesis was examined using 1000 non-parametric bootstrap analyses. GenBank accession numbers of all isolates used to construct the tree are listed in Additional file 1: Table S1.

Fig. 3

Replication of the CDV cycle. Virus particle recognition by host cell receptors (CD150 or nectin-4), RNP release into de cytoplasm, replication, transcription process, and virus particle budding are illustrated

Fig. 4

Principle routes of CDV infection and transmission in hosts. a Infected DCs and alveolar macrophages progress to the local draining lymph node, where they interact with and infect T-cells and B-cells through CD150 that is also expressed on their cell surface. These infected cells further spread to secondary lymphoid organs, causing a secondary viremia. b At the final stages of infection, shedding of infected lymphocytes to distal site of the respiratory tract. These infected lymphocytes interact with the epithelial cell receptor nectin-4, located in the adherent junctions on the basolateral surface of the epithelial cell. Infection in the airway epithelium results in the virus assembly and the release of virions into the airway lumen of the infected lung. c CDV can infect the CNS in some instances and it has been suggested that the receptor nectin-4 has an important role in this infection

Fig. 5

H protein from CDV reference strain, based on MeV crystal structure. Surface representation of the CDV H structure accomplished through homology modelling based on MeV H (PDB: 2RKC), using the software PyMOL, Molecular Graphics System, Version 2.0 Schrödinger, LLC. a In red, residues that potentially interact with mononuclear cell receptors (SLAM); b In blue, positions of CDV H protein that interact with the epithelial cell receptor (nectin-4). The interaction positions of CDV H protein are presented based on the interaction sites of the MeV H protein