Virus-host co-evolution: How specialized should a strain of a multi-host virus be?

Scientists from the Leibniz Institute for Zoo and Wildlife Research (IZW), the Freie Universität Berlin and the University of Göttingen in Germany, the INRS-Institut Armand-Frappier in Canada and Cornell University in USA investigated the 'lock and key' mechanism used by the canine distemper virus (CDV) to gain entry into host cells. In the case of CDV, this mechanism involves the binding of a specific protein of the virus (the CDV haemagglutinin protein, CDV-H) to a specific receptor molecule on the host cell (the signalling lymphocytic activation molecule, SLAM). The authors investigated differences between SLAM receptors in wild and domestic carnivore species. This revealed that SLAM receptors from different species in the dog family (Canidae) were quite similar but that they differed substantially from those of species in other carnivore families such as the cats (Felidae), hyenas (Hyaenidae), martens (Mustelidae), seals (Phocidae) and walruses (Odobenidae). "As the configuration of the 'lock' on the host cell varies considerably between dogs and their close relatives on the one hand and carnivores from other families on the other, we expected that the 'key' used by different strains of CDV to gain entry to host cells would also show variation. Viruses constantly adapt to improve their ability to infect their different host species" comments Klaus Osterrieder (FU Berlin).

The researchers then used cell cultures to investigate the ability of CDV-H proteins from different domestic dog and non-dog strains to gain entry into host cells. This suite of experiments revealed that CDV-H proteins from domestic dog strains performed much better in cell cultures with SLAM receptors from domestic dogs than in cell cultures with SLAM receptors from the African lion or the domestic cat. In other words they exhibited specialist traits. CDV-H proteins from non-dog CDV strains exhibited generalist traits because they performed equally well regardless of which host species SLAM receptor (African lion, domestic cat or domestic dog) was offered to them. Furthermore, as expected of generalists, CDV-H proteins from non-dog strains performed less well in cells that expressed domestic dog SLAM receptors than did CDV-H proteins from domestic dog strains. This variation in performance was not limited to cell entry. It was also found in a further set of cell culture experiments in which either domestic dog and non-dog strains replicated inside cells expressing either domestic dog or non-dog SLAM receptors.

"Gaining entry into host cells with the right 'key' is crucial for successful infection of a host. We therefore wanted to know whether by substituting the amino acid at one specific site in the CDV-H protein previously suggested to be an important component of the 'key' of a specialist strain for the amino acid at this site in non-dog strains would reduce the ability of a dog strain to gain entry into its preferred host, the domestic dog, and simultaneously improve its ability to gain entry into other carnivores" states Veljko Nikolin from the IZW. The research team therefore investigated the functional importance of one amino acid site (549) in the CDV-H protein in different host receptor environments, because this site was known to be under strong positive selection. Domestic dog strains had been previously observed to mostly have the amino acid tyrosine at this site whereas non-dog strains typically had the amino acid histidine at this location. The team found that substituting tyrosine by histidine at site 549 in the CDV-H protein of one dog strain decreased expression of specialist traits and increased expression of generalist traits, thereby confirming the importance of this particular site.

The new findings add substantially to current knowledge on CDV epidemiology by providing evidence for the expression of specialist and generalist traits by CDV strains, unravelling its mechanism and demonstrating fitness trade-offs across carnivore host environments. "There has been a common assumption that canine distemper first evolved in domestic dogs and then spilled over into wild carnivores. Whilst our results are compatible with this idea they also support an alternative explanation -- namely that canine distemper virus was originally a generalist virus in wild carnivores and then later specialist strains evolved as the domestic dog population rapidly expanded together with the human population, thereby providing conditions favourable for strong co-evolution within a homogeneous host environment" explains Marion East, the senior author of the study.

Despite effective vaccines against CDV epidemics regularly occur in domestic dogs in many countries worldwide. CDV infection has been reported in a wide range of wild carnivore species both in free-ranging populations and zoo animals. Clinical signs of CDV include neurological disorders, nasal discharge, high fever, fatigue, and diarrhea.