Anke Brüning-Richardson¹ and Ashley C. Banyard²

¹St James’s University Hospital, Leeds, UK; ²Animal Health
and Veterinary Laboratories Agency, Weybridge, UK

6.1 Introduction

Rinderpest (from the German ‘cattle plague’) was a disease of significant veterinary importance affecting all species of the even-toed ungulates (Artiodactyla). The host range included cattle (both Bos taurus and Bos indicus), but also extended to small ruminants and exotic wildlife, including buffalo, giraffe, deer, kudu, wildebeest and African warthog. The geographical distribution of rinderpest reflected the history of the disease. Outbreaks attributed to the disease were first recorded in the 4th century in Asia, from which it spread to Europe by movement and transportation of cattle and eventually, in the 19th century, to Africa by colonization with concomitant introduction of domestic cattle. By the 20th century, it was endemic in Africa, Asia, the Middle East and the Indian subcontinent. Rinderpest was one of the most economically devastating veterinary diseases. The severity of a European epidemic in the 18th century led to the establishment of the first veterinary college (in Lyon in 1761) as a direct response to control rinderpest by training people as veterinarians. The Great African Pandemic in 1885 alone caused mortality rates of up to 90% in both domestic stock and wildlife, and nearly led to the extinction of the Masai people. A second epidemic from 1979 to 1983 caused the death of over 1 million cattle and it has been estimated that within this period in Nigeria alone more than 500,000 cattle died, causing an economic loss of US$1.9 billion (FAO, 2002).

6.2 Rinderpest Causative Agent

Fig. 6.1. Schematic of the morbillivirus virion.

Of all the morbillivirus proteins, the P protein is antigenically the least conserved (Sheshberadaran et al., 1986) and at the nucleotide level is the most variable gene in the genome. The functioning of the P protein in virus transcription and replication has been inferred from its ability to form distinct complexes with the L and the N proteins during transcription and replication of the genome RNA (Horikami et al., 1992). However, the level of P gene expression seen in infected cells, far in excess of its representation in virions, indicates that as well as functioning in RNA synthesis it is also involved in nucleocapsid assembly.

Importantly, the two non-structural proteins, C and V, are produced from the P open-reading frame (ORF) using alternate mechanisms: C is produced following RNA translation initiation at a second in frame AUG start codon within the P gene, while V is generated following RNA editing within the P ORF to produce a truncated protein. The production of these proteins highlights an evolutionary mechanism by which these viruses maximize coding capacity (Bellini et al., 1985). The morbillivirus C protein has been shown to co-localize with the N, P and L proteins in infected cells, which suggests a role in viral transcription (Sweetman et al., 2001). A recombinant RPV lacking the ability to produce the C protein was found to be defective for growth in a number of cell lines, although the levels of genome and antigenome RNAs produced were comparable to the parent virus. The absence of C from RPV was shown to affect mRNA transcription, suggesting a possible role in initiation, extension or termination of transcription (Baron and Barrett, 2000). A further function identified for the C protein is in counteracting the host response to virus infection through blocking of innate immune responses. A number of paramyxoviruses subvert the host cell’s immune response to infection by blocking interferon (IFN) signaling at different stages and in many viral infections this has been attributed to the C protein. The V protein is produced as a result of a pseudotemplated transcription where a G residue is added to the P gene mRNA during transcription (Lamb and Kolakofsky, 2001). In RPV infections, the V protein interacts with free N protein and is distributed throughout the cytoplasm (Baron and Barrett, 2000) and RPV lacking the V protein, in the presence or absence of the C protein, shows greater genome and antigenome production than wildtype virus (Baron and Barrett, 2000). This points to an influence of the V protein on replication rates and may therefore play a role in viral pathogenesis. The role of the accessory proteins of negative strand viruses is reviewed in Gerlier and Lyles (2011).

The M proteins of all the morbilliviruses sequenced to date have a single ORF of 1005 nucleotides (Mahapatra et al., 2003). The differences seen in the lengths of the M genes of morbilliviruses arise from the presence of a long untranslated GC-rich region present at their 5′ ends. These GC-rich regions are of unknown function, but for RPV, removal of this region seems to have little effect on virus growth in vitro (T. Barrett, personal communication). Many studies have suggested a role for the M protein in virus budding. In this role the M protein is thought to bring together the RNP complexes, which accumulate in the cytoplasm of the infected cell, and the viral glycoproteins, which, through their synthesis on the rough endoplasmic reticulum (RER), localize to the plasma membrane of the cell (Stricker et al., 1994; Wild et al., 1995). This function is conserved among the negative-stand RNA viruses and within the morbillivirus genus the M gene is the most conserved gene (Limo and Yilma, 1990; Curran et al., 1992; Baron et al., 1994).

The polymerase protein performs a number of different functions during the replication of RPV. It acts as an essential subunit of the viral polymerase complex, through interactions with the P and N proteins. L possesses transcriptase and replicase activities as well as acting to cap, methylate and polyadenylate viral mRNAs. Within the morbilliviruses three highly conserved domains that are separated by two hinge regions have been identified. By incorporating c-myc tags at the variable hinge regions of the MeV L protein, it has been shown that these regions vary in their tolerance to insertion and spatial displacement. Abrogation of polymerase function was seen with the insertion of a c-myc tag into the N-proximal hinge region that was attributed to the possible reorientation of a catalytic domain. The second hinge region towards the C-terminus of the L gene is more conserved among the morbilliviruses, but insertion of the tag at this position had no effect on polymerase function. Further studies using the green fluorescent protein (GFP) ORF showed that it was possible to insert the entire GFP ORF into the second hinge region without abolishing L protein function. The incorporation of the GFP-containing polymerase into a recombinant virus did not seriously debilitate its growth in vitro or in vivo. This observation may have many applications for the study of the polymerase unit and virus pathogenicity through the ability to trace the virus in tissues (Duprex et al., 2002; Brown et al., 2005).

6.3 Clinical Signs

6.4 Pathology

Pathological features of rinderpest have been described in detail (Brown and Torres, 1994; Brown et al., 1996; Anderson et al., 1996; Taylor et al., 2005). For the purpose of this chapter, the most common features of rinderpest pathology are summarized here. Perhaps in the most classical form, in cattle and buffalo, rinderpest presented as emaciation and dehydration with signs of diarrhoea and mucopurolent discharge. Congested conjunctiva could be oedematous and corneal ulceration may have occurred. The oral cavity was often affected, but depending on the infecting strain and stage of disease this varied from pinhead or larger necrotic foci to extensive necrosis and gum erosions. The soft palate, pharynx and upper oesophagus might also be affected by necrosis. In some cases, necrosis also occurred in the pillars of the rumen, but with no effect on other areas of the rumen or reticulum. Erosions and haemorrhages might occur in the omasum. The abomasum might also be affected, with evidence of congestion, petechial haemorrhage and oedema. Peyer’s patches might show signs of white necrotic foci, but apart from necrosis and sloughing in neighbouring regions, the small intestines usually remained unaffected. The large intestines might be affected by the presence of blood and blood clots in the lumen; intestinal walls might appear congested and affected by oedema and erosions, which often occurred in the upper colon. The characteristic ‘tiger or zebra striping’ was often seen in the colon and in rectal mucosae in animals with late stage disease. Lungs might be affected by emphysema, congestion and secondary bronchopneumonia. The kidneys were usually unaffected, with some congestion notable in the medulla. However, severe desquamation of the epithelium in the urinary bladder was caused by infiltration of erythrocytes into the underlying stroma.

Fig. 6.2. Pathobiology of rinderpest. Characteristic pathological features: (A) emphysema of the lung; (B) inflamed and haemorrhagic serosal and mucosal surfaces of Peyer’s patches; (C) zebra striping of the intestines – haemorrhages along the crests of the mucosae gave rise to the characteristic striped pattern, which appeared red when recent and green when older; (D) severe congestion and haemorrhage of the fourth stomach; (E) haematological changes during infection (after Anderson et al., 1996). [(A) courtesy of Dr Ashley Banyard; (B–D) courtesy of Jenny Ryder and Professor John Anderson.]