Canine Distemper Virus Spread and Transmission to Naive Ferrets: Selective Pressure on Signaling Lymphocyte Activation Molecule-Dependent Entry

Abstract

Upon infection, morbilliviruses such as measles, rinderpest, and canine distemper virus (CDV) initially target immune cells via the signalling lymphocyte activation molecule (SLAM) before spreading to respiratory epithelia through the adherens junction protein nectin-4. However, the roles of these receptors in transmission from infected to naïve hosts have not yet been formally tested. Towards experimentally addressing this question, we established a model of CDV contact transmission between ferrets. We show here that transmission of wild type CDV sometimes precedes the onset of clinical disease. In contrast, transmission was not observed in most animals infected with SLAM- or nectin-4-blind CDVs, even though all animals infected with the nectin-4-blind virus developed sustained viremia. There was an unexpected case of transmission of a nectin-4-blind virus, possibly due to biting. Another unprecedented event was transient viremia in an infection with a SLAM-blind virus. We identified three compensatory mutations within or near its SLAM-binding surface of the attachment protein. A recombinant CDV expressing the mutated attachment protein regained the ability to infect ferret lymphocytes , but its replication was not as efficient as wild-type CDV. Ferrets infected with this virus developed transient viremia and fever, but there was no transmission to naïve contacts. Our study supports the importance of epithelial cell infection, and of sequential CDV H protein interactions first with SLAM and then nectin-4 receptors for transmission to naïve hosts. It also highlights the selection pressure on the H protein interactions with SLAM. Morbilliviruses such as measles, rinderpest, and canine distemper virus (CDV) are highly contagious. Despite extensive knowledge of how morbilliviruses interact with their receptors, little is known about how those interactions influence viral transmission to naive hosts. In a ferret model of CDV contact transmission, we show that sequential use of the signaling lymphocytic activation molecule (SLAM) and nectin-4 receptors is essential for transmission. In one animal infected with a SLAM-blind CDV, we documented mild viremia due to the acquisition of three compensatory mutations within or near its SLAM-binding surface. The interaction, however, was not sufficient to cause disease or sustain transmission to naive contacts. This work confirms the sequential roles of SLAM and nectin-4 in morbillivirus transmission, and highlights the selective pressure directed toward productive interactions with SLAM.

Camelids and Cattle Are Dead-End Hosts for Peste-des-Petits-Ruminants Virus

“…Interestingly, the pathogenesis found in cattle and camelids (particularly in SAC) in the present study resembles the pathogenesis in ferrets experimentally infected with SLAM-blind CDV [37]. None of the ferrets transmitted the virus to CDV-naïve contact-control ferrets, they presented no clinical signs and no viremia, except for one ferret that showed a transient mild viremia probably due to three compensatory mutations in the H gene of the SLAM-blind virus [37]. Nevertheless, all ferrets elicited a solid humoral immune response that was attributed to low-level replication of CDV in nectin-4 expressing epithelial cells [37].…”

“…None of the ferrets transmitted the virus to CDV-naïve contact-control ferrets, they presented no clinical signs and no viremia, except for one ferret that showed a transient mild viremia probably due to three compensatory mutations in the H gene of the SLAM-blind virus [37]. Nevertheless, all ferrets elicited a solid humoral immune response that was attributed to low-level replication of CDV in nectin-4 expressing epithelial cells [37]. Cattle experimentally infected with PPRV also developed a rapid and solid humoral immune response, while camelids developed a prolonged and lower or no antibody response possibly due to species-specific differences in the immune response (see section humoral immune response) or a lower susceptibility, particularly of dromedaries, to PPRV-infection than cattle.…”

“…The P gene also encodes for the two non-structural proteins C and V [32,33]. Similar to PPRV, a wide host range for the other animal morbilliviruses (canine distemper virus (CDV), cetacean morbillivirus (CeMV) and RPV that infect respectively carnivores, cetaceans and artiodactyls) has been reported [7,8,32,[34][35][36][37]. Attachment of morbilliviruses to cell surfaces is mediated via their H glycoprotein by direct protein-protein interaction with the two major natural host receptors involved in morbillivirus infection: CD150 (signaling lymphocyte activation molecule, SLAM) and nectin-4 [32].…”

“…Fusion activity of the F protein allows virus entry into the cell cytoplasm [32]. SLAM receptors are present on activated lymphocytes, macrophages and dendritic cells (DC) and lead to systemic morbillivirus infection, while the infection of epithelial cells via nectin-4 receptors plays an important role in disease development and virus transmission [37][38][39][40]. The tropism of morbilliviruses for immune cells and lymphoid organs may lead to immune suppression and a higher susceptibility to secondary infections and disease expression [9,39].…”

“…The tropism of morbilliviruses for immune cells and lymphoid organs may lead to immune suppression and a higher susceptibility to secondary infections and disease expression [9,39]. The limited inherent capacity for antigenic variation of morbillivirus glycoproteins [37], and the high conservation of the SLAM and nectin-4 receptors across mammalian species facilitate cross-species transmission of animal morbilliviruses between related mammalian species [35,38].…”