Abstract
Canine distemper virus (CDV), a close relative of measles virus (MV), is widespread and well known for its broad host range. When the goal of measles eradication may be achieved, and when measles vaccination will be stopped, CDV might eventually cross the species barrier to humans and emerge as a new human pathogen. In order to get an impression how fast such alterations may occur, we characterized required adaptive mutations to the human entry receptors CD150 (SLAM) and nectin-4 as first step to infect human target cells. Recombinant wild-type CDV-A75/17red adapted quickly to growth in human H358 epithelial cells expressing human nectin-4. Sequencing of the viral attachment proteins (hemagglutinin, H, and fusion protein, F) genes revealed that no adaptive alteration was required to utilize human nectin-4. In contrast, the virus replicated only to low titres (102 pfu/ml) in Vero cells expressing human CD150 (Vero-hSLAM). After three passages using these cells virus was adapted to human CD150 and replicated to high titres (105 pfu/ml). Sequence analyses revealed that only one amino acid exchange in the H-protein at position 540 Asp→Gly (D540G) was required for functional adaptation to human CD150. Structural modelling suggests that the adaptive mutation D540G in H reflects the sequence alteration from canine to human CD150 at position 70 and 71 from Pro to Leu (P70L) and Gly to Glu (G71E), and compensates for the gain of a negative charge in the human CD150 molecule. Using this model system our data indicate that only a minimal alteration, in this case one adaptive mutation, is required for adaptation of CDV to the human entry receptors, and help to understand the molecular basis why this adaptive mutation occurs.
Highlights
The genus Morbilliviruses of the Paramyxoviridae family comprises the strictly human pathogen measles virus (MV), as well as animal infectious agents such as rinderpest virus (RPV), canine and phocine distemper viruses (CDV and PDV), peste des petits ruminants virus (PPRV), and the cetacean dolphin and porpoise Morbilliviruses (DMV and PMV)
Canine distemper virus (CDV) attachment proteins can utilize human nectin-4 without adaptive alterations For experimental adaptations described in this manuscript we used CDV-A75/17red, a recombinant virulent wild-type CDV, which was originally isolated from the brain of a CDV-infected dog, cloned as a recombinant virus expressing tD tomato red fluorescent protein from the 4th expression cassette, and propagated using Vero-cSLAM cells [20,21,22]
In order to adapt CDV-A75/17red to human nectin-4 we used the human epithelial cell line H358 which is a target cell for measles virus expressing nectin-4, but not CD150 [16,17]
Summary
The genus Morbilliviruses of the Paramyxoviridae family comprises the strictly human pathogen measles virus (MV), as well as animal infectious agents such as rinderpest virus (RPV), canine and phocine distemper viruses (CDV and PDV), peste des petits ruminants virus (PPRV), and the cetacean dolphin and porpoise Morbilliviruses (DMV and PMV). These viruses are all highly contagious and cause systemic infections resulting in devastating diseases in their respective hosts. During the recent outbreaks in monkey breeding farms in China approximately 10,000 animals were infected (25–60% disease incidence) and 5–30% of these died [5]
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