Genetic and molecular basis for low efficacy of vaccine strains against canine distemper virus in Brazil.

Abstract

Canine distemper virus, CDV, is a worldwide distributed disease of the genus Morbillivirus that can affect dogs of all ages, breeds, and both sexes with varying degrees of morbidity and lethality. The virus consists of six structural proteins, of which the Hemagglutinin is responsible for the efficient fusion to the cell membrane, allowing the virus entrance and replication in susceptible animals. The Hemagglutinin protein is responsible for the virus binding to the SLAM and Nectin-4 proteins present on the host cell membrane to start the infection process. This biochemical mechanism is then used to develop vaccines. However, due to the Hemagglutinin amino acid sequence being highly variable in several countries, animals that are vaccinated develop CDV symptoms. To evaluate this low vaccine efficiency in Brazil, this study explores the genetic and molecular basis to understand the differences in the Hemagglutinin phylogenetic profile compared to the vaccine strains. Specifically, Hemagglutinin, SLAM, and Nectin-4 interaction regions are compared to find amino acid mutations responsible for this behavior. For this purpose, a set of molecular modelling programs and protocols was used. Phylogenetic analysis of 102 Hemagglutinin genes highlighted the distances between several groups from the vaccine and the Brazilian strains. To understand the virus recognition specificities, a set of eighteen new tridimensional structures of this receptor was proposed - eleven Brazilian and seven vaccine strains. Despite the high structural similarities, the conformational comparison shows important differences in amino acids on the Hemagglutinin interaction site with SLAM and Nectin-4. Clearly, this lack of the strains circulating in Brazil and the commercial vaccine may explain the protocol failures due to the absence of specific antibodies in the animals to recognize most local CVD, thus evidencing the need for biotechnological efforts to produce vaccines considering a wider range of strains.