Pilot study into the molecular mechanisms of canine distemper virus infection

Abstract

In order to understand how a disease should be prevented, treated and managed, one must understand

both the host and the pathogen, and how they interact with and influence one another. Canine distemper virus (CDV) causes canine distemper, a multisystemic disease that can spread to infect the central nervous system resulting in profound nervous system clinical signs. A myriad of different host species are affected by this virus, with significant variation to be seen in how severely different hosts are affected and how rapidly the disease progresses, even within different individuals of the same host species. Although multiple studies have looked at the virus itself, fewer studies have focused on the host, and particularly the molecular mechanisms of the host response that may underlie the variation in host response to the same virus. In this project I looked at DNA polymorphisms in the SLAM and CD46 host receptors in wild canid and felid species and how this could result in amino acid and ultimately protein differences in these receptors crucial for viral entry into the cell. I found that the DNA and amino acid sequences of canid species grouped separately to those of felid species in terms of sequence similarity, with small DNA sequence differences resulting in different amino

acids between these species. These amino acid differences in turn may partially contribute to different host affinities for CDV at the receptor level by affecting the binding affinity between the virus and the host receptor. The V-domain of the signal lymphocyte activation molecule (SLAM) showed more sequence variability than the selected CD46 exons. Secondly, I compared the gene expression in the brain tissue of healthy dogs to that of dogs infected with CDV. Using RNA sequencing (RNA-Seq) a total of 768 differentially expressed genes were identified between healthy and infected dog brain tissues. Of these, 326 genes were not previously identified by microarray studies that evaluated gene expression associated with CDV infection. It is also worth mentioning that the gene expression differed between different lesion types (as defined histologically) of CDV infection, with certain genes differentially expressed only in each of the lesion types. The variation between lesion types was however smaller than the variation seen between the control versus infected dogs. By looking at both the host differences on a molecular level and studying the differential gene expression in two phases of canine distemper encephalitis, the host-specific differences and variable host affinity observed in CDV infections may be partially explained. This study contributes to improving our understanding of CDV, and the molecular mechanisms in different host species that underlie this disease and its variable manifestations.