PPRV-Induced Autophagy Facilitates Infectious Virus Transmission by the Exosomal Pathway.

Peste des petits ruminants virus (PPRV) is an important pathogen that seriously influences the productivity of small ruminants worldwide. We showed previously that PPRV induced sustained autophagy for their replication in host cells. Many studies have shown that exosomes released from virus-infected cells contain a variety of viral and host cellular factors that are able to modulate the recipient's cellular response and result in productive infection of the recipient host. Here, we show that PPRV infection results in packaging of the viral genomic RNA and partial viral proteins into exosomes of Vero cells and upregulates exosome secretion. We provide evidence showing that the exosomal viral cargo can be transferred to and establish productive infection in a new target cell. Importantly, our study reveals that PPRV-induced autophagy enhances exosome secretion and exosome-mediated virus transmission. Additionally, our data show that TSG101 may be involved in the sorting of the infectious PPRV RNA into exosomes to facilitate the release of PPRV through the exosomal pathway. Taken together, our results suggest a novel mechanism involving autophagy and exosome-mediated PPRV intercellular transmission. IMPORTANCE Autophagy plays an important role in PPRV pathogenesis. The role of exosomes in viral infections is beginning to be appreciated. The present study examined the role of autophagy in secretion of infectious PPRV from Vero cells. Our data provided the first direct evidence that ATG7-mediated autophagy enhances exosome secretion and exosome-mediated PPRV transmission. TSG101 may be involved in the sorting of the infectious PPRV RNA genomes into exosomes to facilitate the release of PPRV through the exosomal pathway. Inhibition of PPRV-induced autophagy or TSG101 expression could be used as a strategy to block exosome-mediated virus transmission.

Mapping the risks of the spread of peste des petits ruminants in the Republic of Kazakhstan.

Peste des petits ruminants (PPR) is a viral transboundary disease seen in small ruminants, that causes significant damage to agriculture. This disease has not been previously registered in the Republic of Kazakhstan (RK). This paper presents an assessment of the susceptibility of the RK's territory to the spread of the disease in the event of its importation from infected countries. The negative binomial regression model that was trained on the PPR outbreaks in China, was used to rank municipal districts in the RK in terms of PPR spread risk. The outbreak count per administrative district was used as a risk indicator, while a number of socio-economic, landscape, and climatic factors were considered as explanatory variables. Summary road length, altitude, the density of small ruminants, the maximum green vegetation fraction, cattle density, and the Engel coefficient were the most significant factors. The model demonstrated a good performance in training data (R2  = 0.69), and was transferred to the RK, suggesting a significantly lower susceptibility of this country to the spread of PPR. Hot spot analysis identified three clusters of districts at the highest risk, located in the western, eastern, and southern parts of Kazakhstan. As part of the study, a countrywide survey was conducted to collect data on the distribution of livestock populations, which resulted in the compilation of a complete geo-database of small ruminant holdings in the RK. The research results may be used to formulate a national strategy for preventing the importation and spread of PPR in Kazakhstan through targeted monitoring in high-risk areas.

Transboundary spread of peste des petits ruminants virus in western China: A prediction model.

In pan Pamir Plateau countries, Peste des petits ruminants (PPR) has brought huge losses to the livestock industry and threaten the endangered wildlife. In unknown regions, revealing PPRV transmission among countries is the premise of effective prevention and control, therefore calls for quantified monitoring on disease communication among countries. In this paper, a MaxEnt model was built for the first time to predict the PPR risk within the research area. The least cost path (LCP) for PPR transboundary communication were calculated and referred to as the maximum available paths (MAP). The results show that there are many places with high-risk in the research area, and the domestic risk in China is lower than that in foreign countries and is mainly determined by human activities. Five LCPs representing corridors among Kazakhstan, Tajikistan, Pakistan, India and China were obtained. This study proves for the first time that there is the possibility of cross-border transmission of diseases by wild and domestic animals. In the future, it will play an important role in monitoring the PPR epidemic and blocking-up its cross-border transmission.

A predictive analysis on the risk of peste des petits ruminants in livestock in the Trans-Himalayan region and validation of its transboundary transmission paths.

Although the Trans-Himalayan region (THR) is an important endemic and rendezvous area of peste des petits ruminants (PPR), monitoring and prevention measurements are difficult to execute because of the rough geographical conditions. Besides, a heterogeneous breeding system and the poor veterinary service of susceptible animals compound the existing problems. Here, we propose a forecasting system to define the key points of PPR prevention and aid the countries in saving time, labor, and products to achieve the goal of the global eradication project of PPR. The spatial distribution of PPR was predicted in the THR for the first time using a niche model that was constructed with a combination of eco-geographical, anthropoid, meteorological, and host variables. The transboundary least-cost paths (LCPs) of small ruminants in the THR were also calculated. Our results reveal that the low-elevation area of the THR had a higher PPR risk and was mainly dominated by human variables. The high-elevation area had lower risk and was mainly dominated by natural variables. Eight LCPs representing corridors among India, Nepal, Bhutan, Bangladesh, and China were obtained. This confirmed the potential risk of transboundary communication by relying on PPR contamination on the grasslands for the first time. The predicted potential risk communication between the two livestock systems and landscapes (high and low elevation) might play a role in driving PPR transboundary transmission.

Combining viral genetic and animal mobility network data to unravel peste des petits ruminants transmission dynamics in West Africa.

Peste des petits ruminants (PPR) is a deadly viral disease that mainly affects small domestic ruminants. This disease threaten global food security and rural economy but its control is complicated notably because of extensive, poorly monitored animal movements in infected regions. Here we combined the largest PPR virus genetic and animal mobility network data ever collected in a single region to improve our understanding of PPR endemic transmission dynamics in West African countries. Phylogenetic analyses identified the presence of multiple PPRV genetic clades that may be considered as part of different transmission networks evolving in parallel in West Africa. A strong correlation was found between virus genetic distance and network-related distances. Viruses sampled within the same mobility communities are significantly more likely to belong to the same genetic clade. These results provide evidence for the importance of animal mobility in PPR transmission in the region. Some nodes of the network were associated with PPRV sequences belonging to different clades, representing potential "hotspots" for PPR circulation. Our results suggest that combining genetic and mobility network data could help identifying sites that are key for virus entrance and spread in specific areas. Such information could enhance our capacity to develop locally adapted control and surveillance strategies, using among other risk factors, information on animal mobility.

Peste des petits ruminants Virus Transmission Scaling and Husbandry Practices That Contribute to Increased Transmission Risk: An Investigation among Sheep, Goats, and Cattle in Northern Tanzania.

Peste des petits ruminants virus (PPRV) causes an infectious disease of high morbidity and mortality among sheep and goats which impacts millions of livestock keepers globally. PPRV transmission risk varies by production system, but a deeper understanding of how transmission scales in these systems and which husbandry practices impact risk is needed. To investigate transmission scaling and husbandry practice-associated risk, this study combined 395 household questionnaires with over 7115 cross-sectional serosurvey samples collected in Tanzania among agropastoral and pastoral households managing sheep, goats, or cattle (most managed all three, n = 284, 71.9%). Although self-reported compound-level herd size was significantly larger in pastoral than agropastoral households, the data show no evidence that household herd force of infection (FOI, per capita infection rate of susceptible hosts) increased with herd size. Seroprevalence and FOI patterns observed at the sub-village level showed significant spatial variation in FOI. Univariate analyses showed that household herd FOI was significantly higher when households reported seasonal grazing camp attendance, cattle or goat introduction to the compound, death, sale, or giving away of animals in the past 12 months, when cattle were grazed separately from sheep and goats, and when the household also managed dogs or donkeys. Multivariable analyses revealed that species, production system type, and goat or sheep introduction or seasonal grazing camp attendance, cattle or goat death or sales, or goats given away in the past 12 months significantly increased odds of seroconversion, whereas managing pigs or cattle attending seasonal grazing camps had significantly lower odds of seroconversion. Further research should investigate specific husbandry practices across production systems in other countries and in systems that include additional atypical host species to broaden understanding of PPRV transmission.

Peste des petits ruminants in Africa: a review of currently available molecular epidemiological data, 2020.

Small ruminants (e.g., sheep and goats) contribute considerably to the cash income and nutrition of small farmers in most countries in Africa and Asia. Their husbandry is threatened by the highly infectious transboundary viral disease peste des petits ruminants (PPR) caused by peste-des-petits-ruminants virus (PPRV). Given its social and economic impact, PPR is presently being targeted by international organizations for global eradication by 2030. Since its first description in Côte d'Ivoire in 1942, and particularly over the last 10 years, a large amount of molecular epidemiological data on the virus have been generated in Africa. This review aims to consolidate these data in order to have a clearer picture of the current PPR situation in Africa, which will, in turn, assist authorities in global eradication attempts.

Identifying Age Cohorts Responsible for Peste Des Petits Ruminants Virus Transmission among Sheep, Goats, and Cattle in Northern Tanzania.

Peste des petits ruminants virus (PPRV) causes a contagious disease of high morbidity and mortality in global sheep and goat populations. To better control this disease and inform eradication strategies, an improved understanding of how PPRV transmission risk varies by age is needed. Our study used a piece-wise catalytic model to estimate the age-specific force of infection (FOI, per capita infection rate of susceptible hosts) among sheep, goats, and cattle from a cross-sectional serosurvey dataset collected in 2016 in Tanzania. Apparent seroprevalence increased with age, reaching 53.6%, 46.8%, and 11.6% (true seroprevalence: 52.7%, 52.8%, 39.2%) for sheep, goats, and cattle, respectively. Seroprevalence was significantly higher among pastoral animals than agropastoral animals across all ages, with pastoral sheep and goat seroprevalence approaching 70% and 80%, respectively, suggesting pastoral endemicity. The best fitting piece-wise catalytic models merged age groups: two for sheep, three for goats, and four for cattle. The signal of these age heterogeneities were weak, except for a significant FOI peak among 2.5-3.5-year-old pastoral cattle. The subtle age-specific heterogeneities identified in this study suggest that targeting control efforts by age may not be as effective as targeting by other risk factors, such as production system type. Further research should investigate how specific husbandry practices affect PPRV transmission.

Peste des petits ruminants in large ruminants, camels and unusual hosts.

Since its first report in 1942, peste-des-petits-ruminants virus (PPRV) has caused several epidemics in a wide range of susceptible hosts around the world. In the last 30 years, the evidence of natural and experimental infections and virus isolation were reported from novel but unusual hosts such as camel, cattle, buffalo, dogs, Asiatic lion and pigs. In addition, PPRV in a potential vector, biting midges (Culicoides imicola), has been reported. Either presented as clinical and/or subclinical infections, the presence of the virus in an extended range of susceptible hosts highlights the cross-species transmission and supports the hypothesis of an endemic circulation of PPRV among susceptible hosts. However, the potential role of large ruminants, camels and unusual hosts for PPRV epidemiology is still obscure. Therefore, there is a need for molecular and epidemiological investigations of the disease among usual and unusual hosts to achieve the goals of disease control and eradication programmes initiated by national and international organisations, such as the FAO and OIE. This review is the first to summarise the scattered data on PPR in large ruminants, camels and unusual hosts to obtain the global scientific communities' attention for further research on epidemiological aspects, not only in its native hosts, but also in large ruminants, camels and other unusual hosts.

Detection of Peste des petits ruminants virus RNA in Culicoides imicola (Diptera: Ceratopogonidae) in Turkey.

An outbreak of Peste des petits ruminants (PPR) occurred in the Antalya Province in Turkey during  October  2015.  The  Antalya  Province  has  suitable  habitats  for  vectors.  There  is  no  information  available  on  the  role  of  Culicoides  spp.  in  the  transmission  of  Peste  des  petits  ruminants virus (PPRV). In this study we investigated the potential role of the Culicoides spp. in  the  transmission  of  PPRV.  Culicoides  were  trapped  throughout  middle  of  October  and  middle of December, 2015. A total of 12 pools of non-engorged females were analysed with real-time RT-PCR targeting the nucleocapsid (N) gene of the PPRV. PPRV RNA was detected in 7 of 12 Culicoides pools. These pools were negative for the bovine/ovine beta-actin mRNA. Culicoides spp. were identified to the species level by sequence analysis of the mitochondrial cytochrome  oxidase  subunit  I  gene.  The  species  of  Culicoides  found  PPRV  positive  was  Culicoides  imicola.  Molecular  characterization  of  field  isolates  from  recent  outbreaks  and  pools of midges that tested positive for PPRV suggests that PPRV replication might occur in Culicoides imicola, and it may have played a role in transmitting PPRV.

Experimental infection of cattle with wild type peste-des-petits-ruminants virus - Their role in its maintenance and spread.

Peste des petits ruminants (PPR) is a major Transboundary animal disease (TADs) of sheep and goats in tropical regions caused by PPRV which can also infect cattle without any clinical signs but inducing seroconversion. However the epidemiological role of cattle in the maintenance and spread of the disease is not known. For the purposes of the present study, cattle were infected with a wild type candidate from each of the four lineages of PPRV and placed in separate boxes. Naive goats were then introduced into each specific box for the 30 days duration of the experiment. The results showed that no clinical signs of PPR were recorded in these infected cattle nor in the in-contact goats. The nasal and oral swabs remained negative. Serum from animals infected with three (3) of the wild type isolates of PPRV showed high percentage inhibition (PI % > 65%) in a cELISA. Only two animals out of three infected with the Nigeria 75/3 strain of lineage 2 (mild strain) had specific anti-PPR antibodies but with PI% values around the threshold of the test. Our findings suggest that cattle are dead-end hosts for PPRV and do not play an epidemiological role in the maintenance and spread of PPRV. In a PPR surveillance programme, cattle can serve as indicators of PPRV infection.

Structure-Guided Identification of a Nonhuman Morbillivirus with Zoonotic Potential.

Morbilliviruses infect a broad range of mammalian hosts, including ruminants, carnivores, and humans. The recent eradication of rinderpest virus (RPV) and the active campaigns for eradication of the human-specific measles virus (MeV) have raised significant concerns that the remaining morbilliviruses may emerge in so-called vacated ecological niches. Seeking to assess the zoonotic potential of nonhuman morbilliviruses within human populations, we found that peste des petits ruminants virus (PPRV)-the small-ruminant morbillivirus-is restricted at the point of entry into human cells due to deficient interactions with human SLAMF1-the immune cell receptor for morbilliviruses. Using a structure-guided approach, we characterized a single amino acid change, mapping to the receptor-binding domain in the PPRV hemagglutinin (H) protein, which overcomes this restriction. The same mutation allowed escape from some cross-protective, human patient, anti-MeV antibodies, raising concerns that PPRV is a pathogen with zoonotic potential. Analysis of natural variation within human and ovine SLAMF1 also identified polymorphisms that could correlate with disease resistance. Finally, the mechanistic nature of the PPRV restriction was also investigated, identifying charge incompatibility and steric hindrance between PPRV H and human SLAMF1 proteins. Importantly, this research was performed entirely using surrogate virus entry assays, negating the requirement for in situ derivation of a human-tropic PPRV and illustrating alternative strategies for identifying gain-of-function mutations in viral pathogens.IMPORTANCE A significant proportion of viral pandemics occur following zoonotic transmission events, where animal-associated viruses jump species into human populations. In order to provide forewarnings of the emergence of these viruses, it is necessary to develop a better understanding of what determines virus host range, often at the genetic and structural levels. In this study, we demonstrated that the small-ruminant morbillivirus, a close relative of measles, is unable to use human receptors to enter cells; however, a change of a single amino acid in the virus is sufficient to overcome this restriction. This information will be important for monitoring this virus's evolution in the field. Of note, this study was undertaken in vitro, without generation of a fully infectious virus with this phenotype.

Identification of Peste des Petits Ruminants Virus, Georgia, 2016.

A phylogenetic analysis of samples taken from reported outbreaks of peste des petits ruminants virus (PPRV) in Georgia revealed a closer relationship to viruses from northern and eastern Africa than to viruses from countries closer to Georgia. This finding has crucial implications for the control of PPRV in the region.

A dynamic model of transmission and elimination of peste des petits ruminants in Ethiopia.

Peste des petits ruminants (PPR), a devastating viral disease of sheep and goats, has been targeted by the global community for eradication within the next 15 years. Although an efficacious attenuated live vaccine is available, the lack of knowledge about the transmission potential of PPR virus (PPRV) may compromise eradication efforts. By fitting a metapopulation model simulating PPRV spread to the results of a nationwide serological survey in Ethiopia, we estimated the level of viral transmission in an endemic setting and the vaccination coverage required for elimination. Results suggest that the pastoral production system as a whole acts as a viral reservoir, from which PPRV spills over into the sedentary production system, where viral persistence is uncertain. Estimated levels of PPRV transmission indicate that viral spread could be prevented if the proportion of immune small ruminants is kept permanently above 37% in at least 71% of pastoral village populations. However, due to the high turnover of these populations, maintaining the fraction of immune animals above this threshold would require high vaccine coverage within villages, and vaccination campaigns to be conducted annually. Adapting vaccination strategies to the specific characteristics of the local epidemiological context and small ruminant population dynamics would result in optimized allocation of limited resources and increase the likelihood of PPR eradication.

Peste des petits ruminants in wild ungulates.

Peste des petits ruminants (PPR) is a contagious viral disease of domestic small ruminants. It also affects wild ungulates but there are comparatively few studies of the incidence of natural infection, clinical signs and pathology, and confirmation of the virus, and in these species. In this article, we list the wild ungulates in which PPRV infection has been confirmed and summarize available information about the presentation of the disease, its identification, and impact of virus on wildlife populations. Considering recent reports of outbreaks by the World Organization for Animal Health (OIE), it is important to understand the transmission of this disease within wildlife populations in PPR endemic regions.

Peste des petits ruminants in China since its first outbreak in 2007: A 10-year review.

Peste des petits ruminants (PPR) is a highly infectious disease of small ruminants and caused by small ruminant morbillivirus (SRMV), formerly called peste-des-petits-ruminants virus (PPRV). This disease is circulating in Africa (except most countries in southern Africa), the Arabian Peninsula, the Middle East, and Central, East and South-East Asia. Peste des petits ruminants is still regarded as an exotic disease in China, where its first outbreak was reported in the Ngari region of Tibet in 2007, but effectively controlled by slaughter, vaccination and animal movement restriction in PPR-infected areas. However, PPR re-emerged in Xinjiang of China in December 2013, rapidly spread into much of China in the first half of 2014, but since then was substantially inhibited countrywide. Phylogenetic analysis shows that SRMVs from China share the highest homology with others from its neighbouring countries, possibly indicating the transboundary transmission of SRMVs. In 2015, a national eradication program for PPR was issued and has been being implemented in China, expecting to achieve a PPR-eradicating aim countrywide by 2020. Here, we reviewed a 10-year history (2007-2017) of PPR in China, including two major outbreaks, its infection in wild species, development of diagnostics and vaccines, and implementation of the national eradication program.

Genetic and epidemiological insights into the emergence of peste des petits ruminants virus (PPRV) across Asia and Africa.

Small ruminants are important components in the livelihood of millions of households in many parts of the world. The spread of the highly contagious peste des petits ruminants (PPR) disease, which is caused by an RNA virus, PPRV, across Asia and Africa remains a major concern. The present study explored the evolutionary and epidemiological dynamics of PPRV through the analyses of partial N-gene and F-gene sequences of the virus. All the four previously described PPRV lineages (I-IV) diverged from their common ancestor during the late-19(th) to early-20(th) century. Among the four lineages, PPRV-IV showed pronounced genetic structuring across the region; however, haplotype sharing among the geographic regions, together with the presence of multiple genetic clusters within a country, indicates the possibility of frequent mobility of the diseased individuals across the region. The gradual decline in the effective number of infections suggests a limited genetic variation, which could be attributed to the effective vaccination that has been practiced since 1990s. However, the movement of infected animals across the region likely contributes to the spread of PPRV-IV. No evidence of positive selection was identified from this study.

Epidemiological investigation into the introduction and factors for spread of Peste des Petits Ruminants, southern Tanzania.

A study was carried out to confirm and identify sources and elucidate factors associated with the introduction of Peste des Petits Ruminants (PPR) in southern Tanzania. This study was conducted in Tandahimba and Newala districts of Mtwara region following suspected outbreak of PPR in the area. Qualitative data were collected using semi-structured questionnaires and in-depth interviews of key informants who included goat and sheep owners with suspected cases of PPR and animal health service providers as well as local administrative authority. Additionally, 216 serum samples and 28 swabs were collected for serological and virological laboratory disease confirmation. The results show that PPR was first introduced in Likuna village of Newala district in February 2009 through newly purchased goats from the Pugu livestock market located about 700 km in the outskirts of Dar es Salaam city. Factors which contributed to spread of PPR included communal grazing and the cheap prices of sick animals bought by livestock keepers for slaughtering in other villages. Laboratory findings confirmed presence of PPR in the area by RT-PCR and serological analysis revealed that seroprevalence was 31%. These findings have confirmed, for the first time, introduction of PPR in southern Tanzania. The presence of PPR poses high risk of southward spread of the disease to other southern African countries in the SADC region thus calling for concerted and collaborative efforts in prevention and control of the disease to avoid losses. Further elaborate studies on the spread, prevalence and risk factors associated with the disease should urgently be investigated.

Peste des petits ruminants: a suitable candidate for eradication?

This year will see the final announcement, accompanied by much justifiable celebration, of the eradication from the wild of rinderpest, the 'cattle plague' that has been with us for so many centuries. The only known rinderpest virus (RPV) remaining is in a relatively small number of laboratories around the world, and in the stockpiles of vaccine held on a precautionary basis. As we mark this achievement, only the second virus ever eradicated through human intervention, it seems a good time to look at rinderpest's less famous cousin, peste des petits ruminants ('the plague of small ruminants') and assess if it should, and could, also be targeted for global eradication.