Since its first report in 1942 in Cote-d'Ivoire, PPR has spread far beyond its origin in Western Africa (Figure 1). In 1999, the prevalence of PPRV antibodies was reported to be 29.2 and 20% in sheep and goats in Turkey/Europe, respectively (18). PPRV reemerged in many African countries including Tanzania (2008 & 2013) (7, 39), Kenya (2014) (40), Democratic Republic of Congo and Angola (2012) (41), and in North Africa such as in Tunisia (2012–2013), Morocco (2015), Algeria (2014) (42–44), and Burundi (2017) (45). In Asia, the virus spread to China in 2007 and again in 2013, spreading rapidly throughout 22 provinces (46–48), and from 2013 to 2014, PPR was also reported from countries surrounding China such as India, Vietnam, and Pakistan where high level of antibody to PPRV was observed in small domestic ruminants and wildlife (49). A risk assessment of PPRV infection in developing countries indicated that ~63% of small ruminants were at risk of infection (50). Therefore, over the last two decades, PPR dissemination has increased exponentially. According to OIE data, PPR was reported in 39 countries in 2007, 43 countries in 2013, and is present in over 70 countries across Asia, Africa, and Europe (Figure 1). As a result, PPR affects 30 million small ruminants yearly, resulting in the economic loss of approximately US$1.2–1.7 billion (42, 43, 51–53). Therefore, following the global eradication of Rinderpest (RP) in 2011, which is the first animal disease and the second disease to have been eradicated in the world, the World Organization for Animal Health (OIE) and Food and Agriculture Organization (FAO) have identified PPR as the next target for eradication by 2030.

As a member of Morbilliviruses, PPRV is a negative-sense, single-stranded RNA virus of ~16,000 nucleotides (nt), which consists of six open reading frames encoding for six structural proteins: Nucleocapsid (N), Phosphoprotein (P), Matrix (M), Fusion (F), Hemagglutinin-neuraminidase (HN), Large RNA-dependent polymerase (L), and two non-structural protein (C and V) (27). The HN and F proteins are embedded in the viral envelope, which constitute the fibers of the virion surface. Only one serotype of PPRV is so far known. However, phylogenetic analysis based on the small region of the N/F gene classifies PPRV into four distinct lineages (I–IV) (41, 54). In comparison to the phylogenetic analysis based on the N, F, M, and HN genes, HN gene seems to be more important to evaluate the epidemiology and the circulating PPRV in endemic areas (55), which may be due to the fact that HN protein is a major determinant for the host tropism. For many years PPR was considered as a variant of RP, specifically adapted for goats and sheep and have lost its virulence for cattle. However, it is now revealed that the PPRV and RP virus (PRV) are biologically and epidemiologically distinct although they are closely related antigenically.

Until 1988, the genus Morbillivirus was thought to comprise only four viruses, namely, Measles virus (MV), PPRV, RPV, and Canine distemper virus (CDV) (56). Later on, three new morbilliviruses have been identified, namely, cetacean morbillivirus (CeMV), phocine distemper virus (PDV) (57–60), and feline morbillivirus (FmoPV or FMV) (61). Previously, clinical description and analysis of the genetic relationship suggested that MV may have originated from an ancestral morbillivirus, and RPV was believed to be the most ancient of morbilliviruses (62–65). Phylogenetic tree of morbilliviruses based on H gene indicated that the genetic relationship of MV and PPRV was the closest of morbilliviruses, and phocine distemper virus (PDV) and CDV were located on the same evolutionary branch (Figure 2). However, the genetic relationship of FmoPV and the other morbilliviruses was highly distant. Molecular evolution analysis of the viruses suggested that the time to the most recent common ancestors (TMRCA) of PPRV/MV/RPV first appeared during 1616 [95% HPD (highest posterior density) 1072–1859] (66). A TMRCA of PPRV was estimated to be in 1904 (95% HPD 1730–1966). Considering the prediction of TMRCA as reasonable and referring to the evolutionary origin theory of measle viruses, it is also possible to estimate that PPRV may have evolved from the ancient virus (RPV). Although, the first description of PPRV was documented in 1942, it was revealed as a new member of the genus Morbillivirus based on the biological and biochemical characteristics in 1979 (67). A study on the phylogenetic analysis of PPRV HN gene (68) exhibited that PPRV strain which caused an outbreak in China in 2007 was not the ancestor virus which caused an outbreak in China in 2013–2014. Around the twenty-first century, genetic diversity of PPRV dramatically increased and caused many outbreaks of PPR as described above. The reasons for this phenomenon are not fully understood, but this could be due to the impact of the RPV eradication program which may promote PPRV to spread rapidly.

PPRV primarily infects domestic goats and sheep, in which mortality can reach up to 100%. However, there are increasing reports of PPRV infection in other domestic and wild animals with or without showing clinical symptoms (Table 1).

PPRV has a broad host range in comparison to the closely related MV and RPV, but it does occur in CDV and CeMV which have been reported to be able to cross the species barriers to infect a wide range of hosts (76, 77). For example, CDV in non-dog hosts has been reported in almost all continents. However, the mechanisms beyond this interspecies infection remain unclear. Like other members of morbilliviruses, PPRV glycoprotein HN, which interacts with the cellular receptors, is necessary for virus attachment. It has been demonstrated that signaling lymphocyte-activation molecule (CD150/SLAM) and poliovirus receptor-like protein 4 (Nectin-4/PVRL4) are two major cellular receptors required for morbilliviruses including PPRV to enter the cells (78). In addition, recently microRNA-218 has been reported to affect PPRV replication by regulating SLAM receptor expression facilitated by HN protein of PPRV in PBMC cells (79). Amino acid variations in the CDV protein which binds cellular receptor may play an important role in species specificity (80). From the evolutionary trees, the evolution of H protein of morbilliviruses appears to be strongly associated with the evolution of the cellular receptor (Figure 2A), especially in Nectin-4. The phylogenetic tree of SLAM and Nectin-4 shows that seals (P. largha) and walrus (O.r.divergens) were located on an evolutionary branch, which indicated that the walrus may be infected with PDV (Figure 2B). However, the fact linked with viruses and hosts which caused the divergence or convergence in the phylogenetic trees remained unclear. Two studies showed that the rate of variation of PPRV HN gene is higher than that of the MV H gene (66, 81). In addition, the variation of PPRVHN gene is faster than that of the genome, which may be the result of the ability of PPRV HN to adapt to large host immune pressure. We have previously reported several positively selective sites on PPRV HN (68), while no positively selective site was found in other morbilliviruses including MV. This indicates that PPRV HN protein does not have much higher stability in comparison with other morbilliviruses, which would have a positive impact on a wide range of host adaptation. On the other hand, a recent phylogenomic analysis based on partial N gene of PPRV with limited sequence data showed a close relationship between PPRV strains recovered from wild and unusual hosts of the same geographical region. From the findings that camel-originated strains from Pakistan clustered close enough to those of domestic origin PPRV reported previously from Pakistan and China (82), it can be inferred that host factors may have a critical role in susceptibility to PPRV infection. On the other hand, SLAM receptor was thought to be related to interspecies infection with the morbilliviruses (64, 83). A study reported that PPRV HN has a high affinity to sheep SLAM based on the analysis of interaction energy and interaction surface contact area (68). When the 188–606 amino acids of PPRV HN were aligned with those of MV H, 41.9% sequence identity and 61.1% sequence similarity were observed. Likewise, the 32–140 amino acids of sheep SLAM (sSLAM)-mice SLAM (mSLAM) and hSLAM (human SLAM)-mSLAM showed 63.7 and 87.3% sequence identity and 79.4 and 93.1% sequence similarity, respectively. This high homology among them promoted the use of the crystal structure of the MV H-SLAM complex (83) as a model to analyze the interaction of PPRV HN protein with SLAM receptor. Simulation of PPRV HN-sSLAM complex showed the presence of a large number of hydrogen bonding interactions in the interface of the complex; D507 on PPRV HN made an intermolecular salt bridge with K78 on sSLAM V domain and also had Pi interactions with PPRV HN residues R191, R533, Y553, and SLAM residues F132, H63, K129 (Figure 3).

Phylogenetic analysis of the receptors showed that the receptors for human and mouse were the most distant compared to goats (Figure 3). Balb/C and Cd1 mice could be experimentally infected by PPRV Nigeria 75/1 strain, but the role of SLAM receptor during PPRV infection in these species is still unknown. If the closest SLAM for evolution has a higher affinity with the PPRV HN, it would be believed that the receptors in other species have also an affinity with the PPRV-HN. Simulation analysis showed that the major binding interface of PPRV HN-hSLAM complex is very similar to that of MV H-SLAM complex (unpublished data). Therefore, we explored the probability of PPRV interspecies infection events from host receptor binding properties using the most distantly related natural hosts of PPRV. Residues I194, D505, D507, D530, R533, F552, and P554 in MV H have been identified as important binding sites for SLAM by multiple mutagenesis studies (84, 85). A comparison of the key amino acids located at the interface of PPRV HN-hSLAM complex showed that residues D505, D507, D530, R533, and F552 were highly conserved in PPRV HN and MV-H proteins (Figure 4). A mutagenesis study confirmed that the β4–β5 hydrophobic groove of H protein head domain is the binding site for both CD46 and Nectin-4, but this hydrophobic groove was not a key binding site for the viral entry through SLAM, which interacts functionally with the propeller blades β5–β6 in MV H (86). Furthermore, this study revealed that hSLAM interacts with an intermolecular β-sheet of PPRV-HN head domain β5–β6 involving the key β64s P191–R195. The mutagenesis and crystal structure study showed that the important residue H61 of mSLAM made a Pi interaction with R533 of MV H, and the contact with E123 of SLAM seemed to stabilize the Pi interaction. Our simulation study shows that R533 of PPRV-HN made a Pi interaction and two hydrogen bonds interact with H61 and E123, respectively. In addition, the crystal structure also showed that R130 had stacking interaction with residue F552 of MV H, while in addition to the formation of Pi interaction, R130 also forms a large number of hydrogen bonds with Y192 and S550 of PPRV-HNw. Considering the receptor, many residues (E50, I60, H61, V63, N77, V82, E123, S127, V128, and F131) are highly conserved in various species. This indicated an affinity of PPRV HN and SLAM of different species by comparing the interaction energy and interaction surface contact area which might help in prediction of the potentiality of the virus to expand to more new hosts species excluding humans.

Besides these factors, Herzog et al. have suggested a relationship between pastoral production and PPRV infection. This study has shown that the animals raised in agropastoral (AP) has seroprevalence rate of 5.8%, whereas 30.7% sero prevalence was observed in pastoral (P) villages in northern Tanzania indicating that even the management system affects the PPRV infection (87). Since unrestricted movements of small ruminants also give rise to massive spread of PPRV as demonstrated in Pakistan by the introduction of disease from infected sheep and goats of Sindh Province (north-west) to Punjab province (central) of Pakistan, health clearance certificate before movement of animals should be emphasized (88).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.