Rinderpest and Peste des Petits Ruminants: Virus Plagues of Large and Small Ruminants
Other possible vectors of the virus for seals included wolves, ferrets, mink and bears that also inhabit areas surrounding the lake. Although not confirmed, the source of the virus is likely to have been terrestrial carnivores, such as wolves, which prey on seal pups. The seals of the Caspian Sea are now critically endangered and, as well as being threatened by CDV infections, they are at risk from hunting for meat. Furthermore, they have suffered a reduction in breeding efficiency due to high concentrations of toxic pollutants such as DDT in their environment Allchin et al.
CDV infection has also been documented in captive seals Lyons et al. A severe die-off of crabeater seals Lobodon carcinophagus in 18 Rinderpest and Peste des Petits Ruminants Antarctica in the s can, with hindsight, be linked to CDV infection although at the time the deaths were attributed to an uncharacterized acute viral infection. In this case, the infection occurred near a scientific field station that kept unvaccinated sledge dogs Laws and Taylor, As there are no terrestrial carnivores in the Antarctic, the dogs were the most probable source of infection.
Another explanation could be transmission by direct contact with terrestrial carnivores in New Zealand or South America during seal migrations. Whatever the source, the virus appears to have established itself in the very extensive crabeater seal population as a subsequent serological survey of Antarctic seals showed this species to have a high prevalence of CDV-specific antibodies Bengtson et al.
Phocine distemper virus Morbilliviruses have also been isolated from marine mammals, including members of the family Pinnipedia seals and the order Cetacea whales, porpoises and dolphins Barrett and Rima, The first morbillivirus with potentially severe ecological consequences for marine mammals was identified in harbour Phoca vitulina and grey Halichoerus grypus seals that died in large numbers off the coasts of northern Europe in Osterhaus and Vedder, This epizootic killed more than 20 seals around northern European coasts, the majority being harbour seals.
At first, based on clinical and antigenic similarities, the seal virus was thought to be CDV, the main pathological feature being acute interstitial pneumonia see Figure 2. The resulting interest in these novel infections in marine mammals meant that molecular resources were employed to characterize the new virus. It was then quickly shown that this new seal virus was most closely related to, but distinct from, CDV and was classified as a new member of the morbillivirus genus and named phocine distemper virus PDV Cosby et al.
The migration patterns of seals allow the virus to be carried over long distances and transmitted to naive seal populations, as was seen in the epizootic which began on the Danish island of Anholt in the Kattegat before spreading to Sweden, the Netherlands, Norway, Germany, the UK and Ireland Jauniaux et al.
In another PDV epizootic occurred in European seals which followed an almost identical course to that of the outbreak, starting at the end of April and again being first detected on the island of Anholt with a population of approximately 12 harbour seals Barrett et al. A month later the virus had spread from the initial focus in the Kattegat through the Skagerrak and then into the Dutch Wadden Sea and the North Sea.
By mid August harbour seal mortalities of epizootic proportions were seen that by mid-September had peaked with almost seals being washed up The morbilliviruses Figure 2. The virus then spread to Scotland, being first identified in a harbour seal found in Dornoch in the Moray Firth. Soon afterwards a small number of dead seals were found in Northern Ireland and along the west coast of Ireland where laboratory tests confirmed the presence of PDV. Further PDV-positive harbour and grey seals were subsequently identified in east and west Scotland including Orkney in late , although, unlike , no noticeable increase in mortality was apparent.
The total death toll in European waters eventually reached over 22 seals Reineking, The source of virus for the outbreak of PDV was, as in , most likely due to contact with infected Arctic seals Dietz et al. Between these two epizootics a minor disease outbreak occurred in in seals along the Belgian and northern French coasts and morbillivirus antigen and nucleic acid were detected in tissues from sick animals but molecular analyses showed that these 20 Rinderpest and Peste des Petits Ruminants Locations of PDV-related deaths in seals in the British Isles during the PDV outbreak.
Figure 2. The source of the virus in both European epizootics was probably Arctic harp seals Phoca groenlandica , which had been seen further south than usual in the winter before the epizootic Dietz et al. Between the epizootics antibody was detected in the serum of seal pups after the disappearance of maternal antibody indicating that the animals were still exposed to PDV for some time after though no disease was observed referred to in Hall, However, the virus could not, and was not, maintained in the European seals from to because of their small population sizes and their scattered distribution.
Morbilliviruses such as measles and rinderpest need a constant supply of naive hosts to maintain endemic infection since lifelong immunity to the virus develops The morbilliviruses 21 in survivors Black, There is growing consensus among some seal biologists that the grey seal populations may act as key vectors in the transmission of PDV between colonies of harbour seals in European waters, especially where large geographical distances are concerned. Harbour seals are known to frequent and return to specific haulout sites whereas grey seals are known to move much greater distances between haulout sites McConnell et al.
Virus transmission is unlikely to occur readily in water as close contact between animals is generally required to facilitate aerosol transmission. Therefore, interactions between the different species at haulout sites may be the key to determining how the epizootics progress. Another important factor may be the relative resistance of grey seals to clinical disease with this virus, possibly enabling PDV to circulate without necessarily causing high mortality, or even showing clinical disease.
Retrospective analyses of archival sera obtained from Arctic seals taken long before the first European PDV outbreak in support the theory that the European PDV infections originated from infected Arctic harp seals as PDV antibodies were found in a high proportion of the archival seal sera from Canadian waters Henderson et al.
Harp seal populations, with an estimated 4 million individuals in Canadian waters alone, are certainly large enough to maintain PDV in circulation. The full host range of PDV is unknown, as are the molecular factors that govern the pathogenic potential of PDV infection in different seal populations, and the virus can cause severe disease in some species whilst other species suffer only mild, subclinical infection Duignan et al.
Coordinated efforts between the various animal health institutes, governmental agencies, private rescue charities and welfare organizations dealing with marine wildlife diseases meant that the European PDV epizootic was efficiently dealt with once the virus had been confirmed as causing the seal deaths on Anholt. The various official bodies concerned and the hundreds of volunteers who helped locate the dead seals made monitoring of the epizootic and collection of samples much easier than in the outbreak, with the networks set up to deal with the previous epizootic being easily re-activated to report on sightings of dead or dying seals and transfer infected animals to quarantine facilities in sanctuaries.
Cetacean morbilliviruses Morbilliviruses have been isolated from several cetacean species including the porpoise morbillivirus PMV and dolphin morbillivirus DMV Kennedy et al. Large die-offs of cetaceans observed on a 22 Rinderpest and Peste des Petits Ruminants number of occasions over the past 15 years have been caused by these viruses.
DMV was responsible for the death of thousands of striped dolphins Stenella coeruleoalba in the Mediterranean sea between and Domingo et al. Due to the difficulty in obtaining good quality samples and good estimates of population size from wild cetaceans the effect of these viruses at the population level is unknown. Also they are not confined to one host species and a virus more closely related to PMV has been isolated from dolphins Taubenberger et al.
Questions remain as to the enzootic source of this virus and the likely vector species. Suspicion has fallen on the pilot whale Globicephala spp. Pilot whale populations have many of the characteristics required of a reservoir and vector for CeMV; they move in large groups pods , have a widespread pelagic distribution and are known to associate with many different cetacean species.
Long finned pilot whales are commonly seen in the Western Mediterranean where the dolphin epizootic was first observed and a high proportion of pilot whales sampled in the mid s showed evidence of infection. Most samples from cetaceans have only been characterized using RT-PCR and limited sequencing data and so it is important to try to obtain more virus isolates from regions remote from Europe to study the extent of variation within this virus type.
Morbillivirus host range The factors determining the barriers to host species jumps by morbilliviruses are unknown. CDV appears to be able to jump from species to species successfully Harder and Osterhaus, However, Mediterranean monk seals were not severely affected during the — epizootic which killed thousands of striped dolphins in that region, despite the fact that CeMV was isolated from the monk seals Osterhaus et al.
The numbers of this once common species have declined alarmingly in the past years as a result of hunting. The morbilliviruses 23 Now the additional pressure of virus infection threatens. A mass die-off of monk seals off the coast of Mauritania in was associated with CeMV infection van de Bildt et al. Infection without overt disease probably also occurred in manatees order Sirenia living off the Florida coast which were found to be serologically positive for CeMV but no unusual mortality that could be virus-related has been reported Duignan et al.
Evolutionary relationships The very high level of antigenic relatedness and sequence similarity seen between the different morbilliviruses indicates that they all evolved from a common ancestor. However, this proposal was made when several of the morbiliviruses had not yet been identified and PPRV was thought to be closely related or simply a different manifestation of RPV. The phylogenetic relationships between the different morbilliviruses are shown in Figure 2.
Similar analyses on the other proteins give the same results. It needs to be stressed however that in the context of rapidly evolving RNA viruses these distances do not imply times since divergence. The evolution of this group of viruses is the subject of a great deal of speculation. Animal populations of the size needed to produce the constant supply of susceptible naive hosts required for a morbillivirus to survive would most likely have been large herds of Asian ruminants, the historic source of rinderpest infection.
For MV the minimum population size that satisfies this condition has been estimated to be about people, but this may be smaller for animals that produce greater litters every year. MV is genetically closest to RPV and it is possible that, when man settled in sufficiently large communities to maintain a morbillivirus, close contact with infected cattle resulted in rinderpest, or a rinderpest-like infection, being passed to humans.
Such a virus may then have evolved to become MV by acquiring pathogenic characteristics for man and other primates and losing them for ruminants. The bar represents nucleotide changes per position. The branch lengths are proportional to the genetic distances between the viruses and the hypothetical common ancestor that existed at the nodes in the tree. Arctic seals may have been infected with CDV several hundreds or several thousands of years ago by contact with terrestrial carnivores such as wolves, foxes, dogs and polar bears, which can carry the virus.
The fact that the two ruminant morbilliviruses, RPV and PPRV, are not closely related emphasizes that narratives about the direction of evolution of these viruses are highly speculative. Similar arguments also apply to speculation about the origin of CeMV. There appears now to be no natural contact between cetacean species and terrestrial species although contact between terrestrial carnivores and stranded cetaceans is possible. Interpretation of this, especially as these viruses are considered to be evolving rapidly, is difficult and this similarity may just be due to chance.
It is possible, with increasing awareness of the importance of these viruses for animal diseases, that other morbilliviruses will be found in the future and techniques are now available which will allow their rapid identification and characterization. Control strategies The existence of only one serotype for each of the morbilliviruses suggests that control of these viruses should be straightforward.
However, individual strains are able to cause a wide spectrum of disease in different species as well as between individual animals of the same species. This effectively means that as yet there is no true distinction between mild and pathogenic strains which in turn makes detection and subsequently control of these viruses difficult. Furthermore, viruses carried by humans and domestic animals can threaten wildlife, particularly where highly endangered species are concerned, and control by vaccination of domestic animals and preventing or limiting contact is the most effective way of ensuring that wildlife will be safeguarded.
The development of live attenuated vaccines was the key to achieving success in controlling diseases such as MV, CDV and RPV since, as with natural infection, the immunity they induce is long-lived and involves a cell-mediated immune response. Protection of vulnerable animals, such as large cats, ferrets and pandas in zoos and seals in sanctuaries, would probably be more acceptable as the animals are confined and would not, if planned, be released until the excretion of vaccine virus had ceased. In any event, there are no currently licensed vaccines for use in these species. During the epizootic a small trial of a commercially available CDV vaccine was carried out and the results are still awaited.
Fortunately, wildlife species quickly recover from such epizootics unless they are critically endangered. References Abu Elzein, E. Allchin, C. Anderson, E. Anderson, J.
Rinderpest and Peste des Petits Ruminants: Virus Plagues of Large and Small Ruminants
Appel, M. In: Virus Infections of Vertebrates. Amsterdam: Elsevier Science. Ata, F. The morbilliviruses 27 Barrett, T. Virology 2 , — In: C. Pfeiffer ed. Florida, Krieger, pp. Sahoo, P. Microbiology Today 30, —4. Barton, A. Bengtson, J. Marine Mammal Sci. New York, Plenum, pp.
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Carmichael, A. In: K. Kipple ed. London: Wiedenfeld and Nicolson, pp. Carpenter, J. Cosby, S. Nature , — Dhar, P. Methods 23 2 , — Dietz, R. Nature , Domingo, M. Duignan, P. El Mjiyad, N. Forsyth, M. Furley, C. Gascoyne, S. Onderstepoort J.
Intervirolog, 11 5 , — Govindarajan, R. Grachev, M. Haas, L.
Haffar, A. Hall, A. Trends Microbiol. Harder, T. Vaccine 13 6 , —3. Harwood, J. Nature , 17— The morbilliviruses 29 Henderson, G. Total Environ. Hernandez, M. Nature , 28—9. Jauniaux, T. Kennedy, S. Kock, R. Laurenson, K. Animal Conservation 4, — Laws, D. Lipscomb, T. Lyons, C. Mahy, B. McConnell, B. McCullough, S. Myers, D. Nanda, Y. Intervirology 23 4 , — Osterhaus, A.
Perry, B. Philippa, J. Reineking, B. Common Wadden Sea Secretariat. Nature , —5. Ross, P. Sabin, A. Pediatrics 90 1 Pt 2 , —9. Shaila, M. Sinclair, A. East Afri. Sutherland-Smith, M. Zoo Wildl. Taubenberger, J.
Van Bressem, M. Visser, I. Vaccine 10 7 , —8. Wild, F. Members of the Paramyxoviridae are indistinguishable in the electron microscope where the virions are seen as pleomorphic particles with a lipid envelope enclosing a ribonucleoprotein RNP core. The RPV virions have a maximum diameter of nm while those of the other ruminant morbillivirus, peste des petits ruminants virus PPRV , are larger and have a mean diameter of — nm Bourdin and Laurent-Vautier, ; Gibbs et al. This chapter will attempt to summarize this work in the context of what is known about the molecular biology of the paramyxoviruses and other negative strand RNA viruses.
Genome organization All morbilliviruses share the same genome organization although their RNA lengths differ slightly, each being just under 16 kb in length. In addition, all morbilliviruses encode two non-structural proteins, V and C, using alternative expression strategies from the P gene transcription unit. This genome organization is similar to other members of the Paramyxovirinae with only the Pneumovirinae having a different gene order Figure 3.
Gaps between each ORF are also shown although not to scale. Each ORF is denoted by an abbreviation for the protein as detailed in the text. For the rubulaviruses and the pneumoviruses and metapneumoviruses an SH small hydrophobic gene is present. The pneumoviruses also have separate NS non-structural genes located upstream of the N protein gene.
Adapted from Lamb and Kolakofsky, Figure 3. These regions contain all the cisacting signals necessary for primary transcription as well as for the production of a full-length positive sense RNA genome copy required for the production of new genome RNA. These regions, and the possible mechanisms by which they interact with the RdRp complex, are discussed in more detail in the next section.
Diallo, unpublished results. Several members of the Paramyxoviridae, including all members of the morbillivirus genus, have a strict genome length requirement. Studies with Sendai virus SeV , using both copy-back and internally deleted DI particles, showed that minigenome replication was only efficient when the length of the RNA genome analogue was exactly divisible by 6.
Subsequently, this rule was also shown to apply to the morbilliviruses Sidhu et al. Initial work on hPIV2 also suggested that the rule of six did not apply to this virus; however, recent studies have shown that recombinant hPIV2 viruses recovered from non-polyhexameric-length antigenomic cDNAs contain a biased distribution of length-correcting mutations Skiadopoulos et al. Full-length genome sequences are now available for most members of the morbillivirus genus Table 3. This stretch of nucleotides before the N ORF start codon acts as a promoter for both the synthesis of virus mRNA and the production of a full-length positive sense antigenome RNA copy, the template for virion RNA synthesis, and as such is referred to as the genome promoter GP.
Recent attempts to define critical residues within the GP and AGP of the respirovirus SeV have identified two distinct domains required for their efficient functioning, suggesting that the promoters are at least bipartite in nature.
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This bipartite model for the promoters is reflected to some extent in all other paramyxoviruses. The second promoter element, present in both the GP and the AGP, is a series of three hexamer motifs present at positions 79—84, 85—90, and 91—96 with respect to the genome ends Tapparel et al. The relative positioning of these elements has been shown to be critical for SeV as displacing them even by six nucleotides abolished promoter function.
Image reconstruction of negatively stained electron micrographs of SeV nucleocapsids show that the nucleocapsid is a left handed helix consisting of 13 N monomers per turn, with each N monomer contacting 6 nucleotides. It is therefore likely that these two regions in the GPs and AGPs of paramyxoviruses directly interact with each other to form a functional promoter unit Figure 3. A similar arrangement is found in the promoters of other paramyxoviruses Murphy and Parks, Changes to the first hexamer motif position 79 in the GP also greatly reduce promoter activity but conservation at this site was not an essential requirement for replication Mioulet et al.
While the GP has two functions, being required for both transcription of virus mRNAs and transcription of a full-length positive sense virus genome replicative intermediate, the AGP performs only a single function, the production of full-length negative sense genomes. The AGP is a much stronger promoter fine tuned for replication, a fact that has been demonstrated experimentally through analysis of the amount of full-length genome and antigenome sense RNAs produced during infection in vitro.
Udem and Cook reported a ratio of two- to three-fold excess of genomic over antigenomic RNA for CDV and for other paramyxoviruses this can be up to 5- to 10fold higher Whelan and Wertz, a. The first three protein hexamers and the three hexamers containing the conserved C residues in the respiroviruses and the morbilliviruses are more darkly shaded. The spatial arrangement of the SeV nucleocapsid structure suggests that the three conserved C residues at positions 79, 85, and 91 present in hexamers N14, N15 and N16, respectively lie directly above and interact with N subunits 1, 2 and 3 as indicated by the dashed lines.
Similar enhancer elements have not been identified in morbilliviruses. Transcription After virus fusion with the cell membrane the nucleocapsid is released from the envelope and transcription begins in the cytoplasm Plate 1—see colour plate section. How the RdRp accesses the template RNA is unclear as Molecular biology of the morbilliviruses 37 the association of the nucleocapsid protein with the RNA is strong; it can resist even the high salt conditions required for caesium chloride CsCl density gradient purification. Access is thought to be made possible either by a reversible transition in the protein-RNA association or by local displacement of N during transcription, as occurs in the separation of the two strands of DNA during its transcription for review, see Kolakofsky et al.
A third possibility, which is suggested to be the case for VSV, is that N associates with the RNA at the sugar—phosphate backbone thus leaving the Watson—Crick positions free to act as a template for transcription by the RdRp Iseni et al. In transcription mode access of the RdRp to downstream transcription units is, therefore, entirely dependent upon completion and release of a newly synthesized copy of the mRNA from the preceding unit.follow
Rinderpest and Peste des Petits Ruminants: Virus Plagues of Large and Small Ruminants
This leads to a transcriptional gradient being set up whereby less mRNA is transcribed the further a gene is distant from the GP. This has been shown experimentally with VSV where, using reverse genetics, the positions of the transcription units along the genome were changed relative to the GP Wertz et al. No estimation was made for the L mRNA since the quantity of this messenger is too low to be measured accurately.
In the stop—start mode the IG sequence is not normally transcribed as it acts as a signal to the polymerase indicating the end of the transcription unit and, if this signal is correctly recognized by the polymerase, only monocistronic mRNA is synthesized. However, the transcription of negative strand RNA genomes is not always completely accurate and both monocistronic and polycistronic mRNAs are produced, although only the first cistron is ever translated from a bicistronic mRNA for review, see Horikami and Moyer, ; Wong and Hirano, Before genome sequences were determined these transcriptional aberrations were used to map the gene order for these negative strand viruses.
Experiments carried out with VSV show that the conserved trinucleotide AGG at the start of the mRNAs is critical for efficient gene expression and contains essential signals for the correct processing of the nascent mRNA and in its absence the majority of transcripts are prematurely terminated Stillman and Whitt, , This conserved trinucleotide probably also forms part of the signal for capping and methylation of the messenger RNA. The conserved tract of four U residues, which always precedes the IG, signals the polyadenylation of the mRNA transcripts.
This polyadenylation signal may have other functions, at least in VSV, as not only does it indicate the end of the upstream mRNA, but it appears necessary for efficient transcription of the downstream transcription unit Hinzman et al. Other studies suggest that the number of U residues reflects the variable lengths of the mRNA poly-A tails and it has been hypothesized that this variation in U tract-length may affect the efficiency of transcription termination in the paramyxoviruses Rassa et al.
These mechanisms have not been investigated in detail for the morbilliviruses. Based on these observations, Castaneda and Wong suggested that transcription of the MV genome might start directly at the N protein start in vivo. The mechanism by which the polymerase complex makes the choice between initiation sites, however, is still not clear.
It could be determined by modifications either to the RdRp or the template or by a combination of both Barr et al. The involvement of cellular factors has also to be considered since in vitro transcription of the MV genome is known to be stimulated by cytoplasmic cell extracts Moyer et al. During transcription the paramyxoviruses exhibit what would seem to be an evolutionary adaptation to maximize coding capacity. Here, the P gene uses two different mechanisms to generate more than one protein from its Molecular biology of the morbilliviruses 39 transcription unit and so, unlike the other five transcription units, is not equivalent to one gene.
As well as the full length P protein, synthesized from the first initiation codon, a second protein, the C protein, is also translated. This results from leaky ribosomal scanning whereby the first AUG initiation codon is ignored, translation instead starting at the second initiation codon, 19 nucleotides downstream of the first Bellini et al. The second non-structural protein encoded from the P gene is derived from the P transcription unit by a novel mechanism. This insertion causes a translational frameshift and the V protein, a C-terminally truncated cysteine-rich form of the P protein, is generated Schneider et al.
In rare cases it is thought that this mechanism can cause the insertion of two extra G residues, generating a further smaller and poorly characterized protein, the W protein. This suggests that this region may be more important in vivo, perhaps through interactions with host cell proteins somehow regulating viral transcription, replication or translation.
As a consequence the synthesis of full-length antigenome RNA and N protein production must be linked Gubbay et al. In the s a self-regulatory model was proposed Blumberg and Kolakofsky, ; for review see Banerjee, In this model, which was widely accepted for many years, the unassembled N protein plays the major role in switching the RdRp between its transcriptase and replicase functions. The RdRp would then transcribe the genes in tandem, recognizing all of the cis-acting stop, polyadenylation, IG and start sequences, to produce a full complement of mRNAs.
This theory accords with the observation made by Wertz et al. However, increasing the amount of N protein produced in a minireplicon system for respiratory syncytial virus RSV does not enhance the rate of replication relative to transcription Fearns et al. It is now thought more likely that transcription and replication require different sets of accessory proteins to interact with the RdRp to form either a transcriptase or a replicase complex. Gupta et al. It has long been understood that both L—P and N—P complexes are essential for the replication process and that association of P with N maintains the latter in a soluble form ready to encapsidate newly synthesized viral RNA, but not cellular RNAs, as the N—P complex requires an encapsidation signal to bind the RNA Horikami et al.
In the Gupta model, the transcriptase complex is formed by an RdRp associated with an L-Poligomer and possible host cell factors and differs from the replicase which is formed from a tripartite association with Molecular biology of the morbilliviruses 41 the additional involvement of an N-Poligomer. In the Kolakofsky model the transcriptase complex is proposed to consist of the RdRp with an L-Poligomer and a free Poligomer which will bind directly to the genomic RNA while in the replicase complex the L-Poligomer is associated with an N-Poligomer.
In both models the N protein plays a major role in determining the replicase activity. The M protein may also be involved in the regulation of RdRp activity and the inhibitory effect of M on VSV transcription has been known for many years see review by Banerjee, The inhibitory effect of M seems to be independent of its role in virus assembly and budding, the amino acid residue at position 58 in the RV M protein being critical for this function Finke and Conzelmann, The exact mechanism underlying M protein inhibition is not yet fully understood but, if the transcriptase complex is functionally different from the replicase complex, it might target the transcriptase directly and leave the replicase unaffected.
This inhibition by M has not been investigated for the other morbilliviruses. Virus structural proteins The N protein The N protein is the major viral structural protein in the non-segmented negative strand RNA viruses. However, for the rhabdovirus RV , both RNA transcription and replication are reduced if the N protein is not phosphorylated Yang et al. Sequence data are now available for all the morbillivirus N proteins.
The nascent N protein when expressed alone, either in mammalian, insect or bacterial cells, quickly associates into nucleocapsid-like aggregations to form a more condensed form of the protein Mitra-Kaushik et al. These N-protein aggregations can 42 Rinderpest and Peste des Petits Ruminants be detected in both the cytoplasm and the nucleus of the transfected cells. The signal required for nuclear transport is located in the first 80 amino acids as demonstrated for CDV by Yoshida et al. Diallo, unpublished data.
The region involved in N protein self-assembly has been mapped to what is termed the Ncore Bankamp et al. The C-terminal variable fragment IV NTail , which is about 12 kDa, is exposed on the surface of the protein and is easily cleaved by trypsin digestion. On removal of the NTail from the protein, the Ncore still retains the ability to form nucleocapsid-like structures Giraudon et al.
The C-terminal residues — are involved in binding to the P protein Bankamp et al. The C-termini of morbillivirus N proteins also interact with cellular regulatory proteins such as heat shock protein Hsp72, interferon regulator factor IRF-3, and a novel cell surface receptor tenOever et al. It is a multifunctional protein, which binds both the N and L proteins and acts as a chaperone to keep the N in a soluble form for binding to the RNA. The P proteins are much smaller 54—55 kDa than the values determined from polyacrylamide gels where they migrate at 72—86 kDa Diallo et al.
This aberrant migration can be attributed to the post-translational phosphorylation of the protein which is rich in serine and threonine. Of the three serine residues positions 49, 38 and identified as potential phosphorylation sites in the RPV P protein, only that at position is conserved in all morbilliviruses Kaushik and Shaila, Molecular biology of the morbilliviruses 43 The C-terminal region of paramyxovirus P proteins contains the domain that interacts with the exposed C-terminus of the N protein Ryan and Portner, ; Huber et al.
Harty and Palese a have mapped the N binding sites of MV P to two regions, one present in the N-terminal amino acids, the other being more precisely defined as residues — at the C-terminus. Using the yeast two-hybrid system it was shown that an N-terminal 60 amino acid region and a C-terminal amino acid region — are simultaneously involved in an N—P interaction in RPV Shaji and Shaila, Furthermore, reflecting the fact that this region has important functions, the C-terminal half of P is more conserved than the N-terminal half, residues — being the most conserved.
While the N protein of morbilliviruses is found both in the cytoplasm and in the nucleus, when complexed with the P protein, it is found exclusively in cytoplasm Huber et al. It has been suggested that the C-termini of both the N and P proteins of MV belong to a class of intrinsically disordered proteins that fold to a defined structure only upon binding to their partners Johansson et al. This class of unfolded, or intrinsically unstructured proteins, have little or no ordered rigid structure under physiological conditions and are usually involved in key biological processes such as cell cycle control, transcription and translation regulation, transport, etc.
Wright and Dyson, ; Iakoucheva et al. This gives the advantage of increased plasticity since they can bind many distinct targets, although with a low affinity. Because the domains involved in the N—P interactions are naturally unstructured, the complex they form is not very stable, allowing a dynamic and rapid transition between two states, and formation and breakage of links to facilitate the progress of the polymerase in copying the template RNA and encapsidating the nascent RNA during replication Johansson et al.
The P protein may also be required to facilitate the proper folding of the L-protein, since in SeV the P protein must be co-expressed with L to keep it stable Horikami et al. The M protein It is well established that epithelial cells are polarized, having distinct apical and basolateral domains which are different in structure, for example lipid and protein composition, and possibly function Rodriguez-Boulan and Nelson, It has been shown in MV that maturation and release of virus particles 44 Rinderpest and Peste des Petits Ruminants occur at the apical surfaces of epithelial cells although the two viral glycoproteins are found mainly at the basolateral surfaces Blau and Compans, ; Maisner et al.
The M protein serves as a bridge between the external surface viral proteins H and F and the internal nucleocapsid and as such plays an important role in the formation of new virus particles which are released from the infected cell by a process of budding from the cell surface for review, see Simons and Garoff, ; Peeples, The M protein is known to direct the glycoproteins to the apical surfaces of polarized cells and any that escape capture by M accumulate on basolateral surfaces due to a tyrosine-dependent sorting signal located in their cytoplasmic tails.
MV viruses bearing a tyrosine point mutation in this sorting signal are unable to propagate by formation of syncytia in polarized cells in vitro and in vivo Moll et al. Blood cells such as macrophages which disseminate the virus in the host are likely to be infected upon contact with the basal surface of epithelial cells by direct cell—cell fusion, which is an alternative way for MV to infect cells Naim et al.
When conservative substitutions are taken into account, the similarities of the different morbillivirus proteins is higher Table 3. Only a stretch of 20 residues lying between positions and varies significantly between morbilliviruses Haffar et al. A pivotal role is played by M in ensuring efficient incorporation of nucleocapsids into virions for HIPV. Here, a process whereby the M protein interacts with the F and H proteins through their cytoplasmic tails and with the RNP complexes in the cytoplasm brings these virus components together at the cell surface to form new virus particles Coronel et al.
Table 3. Molecular biology of the morbilliviruses 45 Budding of morbilliviruses may occur at specialized membrane regions for which the M protein has more affinity; for example lipid raft microdomains are the potential locations for MV assembly Manie et al. Actin filaments, responsible for cellular transport, also are required for virus budding and it has long been known that destruction of actin filaments prevents MV budding Stallcup et al. Actin is highly concentrated in apical microvilli in epithelial cells Riedl et al. The outcome of this process is the release of virus particles at the apical domain of epithelial cells which will then be excreted by the host to infect neighbouring cells or a new host.
The M protein or, more precisely, defects in its synthesis, are hypothesized to contribute to the molecular basis of a fatal complication of MV infection, subacute sclerosing panencephalitis SSPE. The invariably fatal outcome of SSPE has meant that a considerable effort has been put into understanding its pathogenesis and the molecular events leading to persistent infection in the brain. In contrast, the F and H genes, as with the M, contain mutations which are also believed to influence the development of disease.
These defects in sequence arise through biased hypermutation and such defects prevent completion of the viral replication cycle thus enabling establishment of a non-productive persistent infection in the brain. The low levels of virus replication in the brain may allow defects to build up in genes that are not essential for replication or these mutations may be explained by the release from the selective pressure normally exerted on viral genes. In SSPE pathogenesis, the virus only needs to replicate and spread from cell to cell, without the necessity to produce infectious progeny.
In fact altered transcription gradients have been observed in SSPE infections where transcription of the non-essential glycoproteins and M protein are more steeply downregulated Cattaneo et al. Video : How to eliminate PPR. Interview : PPR's effects on food security and the strategy to eradicate it. Audio : Peste des Petits Ruminants : Targeting total eradication of a devastating livestock disease. The strategy is in line with the principles of the successful campaign that led to the global elimination of rinderpest. Prevention and control measures are essential for the containment of PPR.
These measures may include animal movement control, institution of quarantine on affected or suspect farms, and medical prophylaxis vaccination around field outbreaks and in high risk areas. FAO works with both governmental and non-governmental organizations, civil society, the private sector, research institutions and academia to improve capacities in livestock management, from disease preparedness to animal husbandry, sustainable production and animal welfare. Together with its partners, the Organization supports veterinary services and vulnerable livestock farmers to increase their knowledge and skills.
They also lack reservoir species outside the infected populations. And diagnostic tests, surveillance protocols, and control and eradication programs exist for both. In , Dr. Walter Plowright began field use of an attenuated live-virus rinderpest vaccine. Such vaccination made rinderpest eradication a practical objective, according to the World Food Prize Foundation, which awarded the British veterinarian the World Food Prize in Peste des petits ruminants virus was identified in West Africa in the early s. You may be trying to access this site from a secured browser on the server.
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