Marine Morbilliviruses: Diversity and Interaction with Signaling Lymphocyte Activation Molecules

Abstract

Epidemiological reports of phocine distemper virus (PDV) and cetacean morbillivirus (CeMV) have accumulated since their discovery nearly 30 years ago. In this review, we focus on the interaction between these marine morbilliviruses and their major cellular receptor, the signaling lymphocyte activation molecule (SLAM). The three-dimensional crystal structure and homology models of SLAMs have demonstrated that 35 residues are important for binding to the morbillivirus hemagglutinin (H) protein and contribute to viral tropism. These 35 residues are essentially conserved among pinnipeds and highly conserved among the Caniformia, suggesting that PDV can infect these animals, but are less conserved among cetaceans. Because CeMV can infect various cetacean species, including toothed and baleen whales, the CeMV-H protein is postulated to have broader specificity to accommodate more divergent SLAM interfaces and may enable the virus to infect seals. In silico analysis of viral H protein and SLAM indicates that each residue of the H protein interacts with multiple residues of SLAM and vice versa. The integration of epidemiological, virological, structural, and computational studies should provide deeper insight into host specificity and switching of marine morbilliviruses.

Keywords: cetacean morbillivirus; host specificity; marine mammal; morbillivirus; phocine distemper virus; receptor; signaling lymphocyte activation molecule.

Figure 1

Locations of reported phocine distemper virus infections of pinnipeds and cetacean morbillivirus infections of cetaceans. Numbers indicate references. P (red), pinnipeds; C (black), cetaceans.

Figure 2

Phylogenetic trees of full-length signaling lymphocyte activation molecules (SLAMs) (a) and full-length morbillivirus hemagglutinin (H) proteins (b). Neighbor-joining methods were implemented in MEGA7 [142,143]. The bootstrap probabilities with 500 replications are shown at the nodes. Respective pairs of host animals and corresponding morbilliviruses are shown as squares with the same color and same alphabetic notations: A, large ruminants; B, small ruminants; C, cetaceans; D, felids; E, canids; F, pinnipeds; G, primates. Morbilliviruses have not been identified in manatees and elephants (H, red dashed box). The amino acid sequences of full-length SLAMs were obtained from the Data Bank of Japan: cow (Bos taurus, AAK61860.1); buffalo (Bubalus bubalis, ABB58751.1); sheep (Ovis aries, NP_001035378.1); goat (Capra hircus, ABB58752.1); minke whale (Balaenoptera acutorostrata, XP_007171815.1); sperm whale (Physeter catodon, XP_007124119.2); Pacific white-sided dolphin (Lagenorhynchus obliquidens, BAH10670.1); killer whale (Orcinus orca, BAH1067.1); bottlenose dolphin (Tursiops truncatus, XP_004327894.1), tiger (Panthera tigris altaica, XP_007092436.1); cat (Felis catus, BAN42597.1); dog (Canis lupus familiaris, AAK61857.1); red fox (Vulpes vulpes, ACD47119.1); walrus (Odobenus rosmarus, BAH10673.1); spotted seal (Phoca largha, BAH10672.1); harbor seal (Phoca vitulina, AYR16904.1); rhesus monkey (Macaca mulatta, XP_001117605.1); human beings (Homo sapiens, NP_003028.1); chimpanzee (Pan troglodytes, XP_513924.2); cotton-top tamarin (Saguinus oedipus, AAG02017.1); manatee (Trichechus manatus, BAH10674.1); and elephant (Loxodonta africana, XP_003415237.1). The amino acid sequences of morbillivirus full-length H proteins were obtained as follows: MV Edmonston AIK-C strain (BAB60866.1); MV 9301B strain (BAA33872.1); RPV Kabete O strain (AAA47401.1); RPV RBOK strain (CAA83182.1); PPRV Turkey 2000 strain (YP_133827.2); PPRV Ghana/NK1/2010 strain (AID07002.1); DMV Bph/2013 strain (AOZ56997.1); DMV (NP_945029.1); PMV 2990 strain (AAT84062.1); PMV IRL/88 strain (ACV50419.1); CDV Lion94SNP strain (AFQ38775.1); CDV 5804/Han90 strain (CAA59359.1); CDV Baikal seal strain (CAA59357.1); CDV Onderstepoort vaccine strain (AAG30920.1); and PDV Ulster/88 strain (BAA01207.1). Each amino acid sequence alignment was generated using ClustalW version 1.8.

Figure 3

Ribbon representation of the three-dimensional (3D) structures of signaling lymphocyte activation molecules (SLAMs) from killer whales (Orcinus orca) and cotton-top tamarins (Saguinus oedipus). The 3D models were constructed by homology modeling based on the crystal structure of the complex between MV-H and the cotton-top tamarin SLAM-V [148,150]. (a) Blue and green models show the two SLAM extracellular domains of killer whales forming a homophilic dimer. β-strands are indicated by blue and green arrows and disulfide bonds are shown as yellow lines. The red arrow indicates the direction of view of the interface for morbillivirus binding as shown in (b) and (c). (b) Interface of the killer whale SLAM from the view of the red arrow in (a). Four β-strands are indicated as C, C’, F, and G. The amino acids that potentially interact with the viral H protein are shown along with their position numbers. The amino acid positions correspond to those of the MV-H–SLAM-V crystal structure [148]. (c) As a reference, the cotton-top tamarin SLAM interface is shown. The four binding sites (S1–S4) present in the crystal structure [148] are marked with dotted circles. The residues involved in these four binding sites are colored differently (site 1—mint green; site 2—cyan; site 3—red; site 4—orange) with colored atoms (black for carbon, blue for nitrogen, and red for oxygen). This figure was modified from Shimizu et al. [150].

Figure 4

Alignment of the 35-residue signaling lymphocyte activation molecule (SLAM) subsequence important for interaction with the hemagglutinin (H) protein along with the corresponding phylogenetic tree. The mammalian phylogenetic tree was created by merging a conventional mammalian tree [140,141], the detailed cetacean tree generated using the short interspersed elements method [159,160,161], and the detailed tree of Caniformia generated using maximum likelihoods method [162]. Cyan, green, and pink boxes, respectively, indicate positively, weak-positively, and negatively charged amino acids. * Stejneger’s beaked whale, ** Pygmy sperm whale.

Figure 5

Schematic diagram of the relationships between morbillivirus species and their host animals. The hosts of each morbillivirus species are surrounded by dotted squares. The names of the various morbilliviruses are given in different colors. Residues of the 35-residue signaling lymphocyte activation molecule (SLAM) subsequence involved in hemagglutinin (H) protein binding that are not conserved among the host animal species are shown. Conserved residues or conservative amino acid substitutions are not shown. Thick colored arrows indicate recent host expansion beyond the order, and the dotted arrow indicates that the inferred transmission event during the evolution of MV.