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Porcine reproductive and respiratory syndrome virus (PRRSV) has been epidemic more than 30 years in America and 20 years in China. It is still one of the most important causative agents to the worldwide swine industry. Here, we systematically analyzed the prevalence status of PRRSV in China by a molecular epidemiological perspective. Now both PRRSV-1 and PRRSV-2 are circulating and approximately more than 80% of pig farms are seropositive for PRRSV. For PRRSV-2, there are four lineages (lineage 1, lineage 3, lineage 5, lineage 8) circulating in the fields. Lineage 8 (CH-1a-like) and lineage 5 (BJ-4-like) appeared almost at the same time during 1995-1996. Notably, BJ-4 shares 99.6% and 99.8% identity with VR2332 and RespPRRS MLV, respectively. It means that lineage 5 is likely to be imported from America. Now highly pathogenic PRRSV (HP-PRRSV) which was considered to be evolved from local diversity of lineage 8 strains is predominant with different variants. Lineage 3 appeared in 2010 which is mainly sporadic in south of China. Lineage 1, also known as NADC30-like strains in China, has been prevalent since 2013 and leads to PRRS pandemic again. For PRRSV-1, although sporadic at present, more than 9 provinces/regions have been reported. All the circulating strains belong to subtype I. It should be paid more attention since there are no vaccines available. Our analysis would help to deeply understand the prevalent status of PRRSV in China and provide useful information for prevention and control of porcine reproductive and respiratory syndrome (PRRS).

•Porcine reproductive and respiratory syndrome (PRRS) is a chronic and economically devastating disease of pigs since the late 1980s.•Although modified live-attenuated PRRSV (PRRSV-MLV) vaccines have been used since 1995, control of PRRS globally is still a challenge.•PRRSV-MLV provides incomplete protection against existing and emerging genetically variant field isolates.•Promising approaches to improve PRRSV-MLV efficacy, are under experimental study.•This review highlights the current status and future directions of infectious PRRSV vaccine. Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) was reported in the late 1980s. PRRS still is a huge economic concern to the global pig industry with a current annual loss estimated at one billion US dollars in North America alone. It has been 20 years since the first modified live-attenuated PRRSV vaccine (PRRSV-MLV) became commercially available. PRRSV-MLVs provide homologous protection and help in reducing shedding of heterologous viruses, but they do not completely protect pigs against heterologous field strains. There have been many advances in understanding the biology and ecology of PRRSV; however, the complexities of virus-host interaction and PRRSV vaccinology are not yet completely understood leaving a significant gap for improving breadth of immunity against diverse PRRS isolates. This review provides insights on immunization efforts using infectious PRRSV-based vaccines since the 1990s, beginning with live PRRSV immunization, development and commercialization of PRRSV-MLV, and strategies to overcome the deficiencies of PRRSV-MLV through use of replicating viral vectors expressing multiple PRRSV membrane proteins. Finally, powerful reverse genetics systems (infectious cDNA clones) generated from more than 20 PRRSV isolates of both genotypes 1 and 2 viruses have provided a great resource for exploring many innovative strategies to improve the safety and cross-protective efficacy of live PRRSV vaccines. Examples include vaccines with diminished ability to down-regulate the immune system, positive and negative marker vaccines, multivalent vaccines incorporating antigens from other porcine pathogens, vaccines that carry their own cytokine adjuvants, and chimeric vaccine viruses with the potential for broad cross-protection against heterologous strains. To combat this devastating pig disease in the future, evaluation and commercialization of such improved live PRRSV vaccines is a shared goal among PRRSV researchers, pork producers and biologics companies.

•Five PRRSV vaccines have been tested for the efficacy to NADC30-like PRRSV challenge.•Vaccinated pigs had improved clinical manifestations compared to unvaccinated ones.•However, vaccinated pigs developed similar viremia and suffered pathological lesions.•PRRSV vaccines could not provide complete protection to NADC30-like PRRSV infection. NADC30-like PRRSV has been recently reported and became endemic in vaccinated pig herds in China. The outbreaks of disease in vaccinated pigs indicated the inefficacy of commercial PRRSV vaccines. In this study, five commercial PRRSV vaccines that have been widely used in China were used to evaluate the efficacy to a NADC30-like PRRSV infection. The vaccinated pigs were challenged with HNjz15, a NADC30-like PRRSV at 28days post vaccination. Compared to unvaccinated pigs, the vaccinated pigs clinically shortened the period of fever with less pig numbers of clinical manifestations and had improved body weight gain at the end of the study. However, the vaccinated pigs developed viremia with similar kinetics and suffered pathological lesions in lung and lymphoid tissues as the unvaccinated pigs. The virus load in tonsil, lung and lymph nodes detected by immunohistochemistry staining in vaccinated pigs was also similar to that in unvaccinated pigs which indicated the inability of vaccination to eradicate the virus from tissues of vaccinated pigs. Therefore, the above results suggested current commercial PRRSV vaccines could not provide complete protection to the NADC30-like PRRSV infection.

Porcine reproductive and respiratory syndrome (PRRS) is one of the most significant swine viral infectious diseases worldwide. Vaccination is a key strategy for the control and prevention of PRRS. At present, the NADC30-like PRRSV strain has become the predominant epidemic strain in China, superseding the HP-PRRSV strain. The existing commercial vaccines offer substantial protection against HP-PRRSV, but their efficacy against NADC30-like PRRSV is limited. The development of a novel vaccine that can provide valuable cross-protection against both NADC30-like PRRSV and HP-PRRSV is highly important. In this study, an infectious clone of a commercial MLV vaccine strain, GD (HP-PRRSV), was first generated (named rGD). A recombinant chimeric PRRSV strain, rGD-SX-5U2, was subsequently constructed by using rGD as a backbone and embedding several dominant immune genes, including the NSP2, ORF5, ORF6, and ORF7 genes, from an NADC30-like PRRSV isolate. In vitro experiments demonstrated that chimeric PRRSV rGD-SX-5U2 exhibited high tropism for MARC-145 cells, which is of paramount importance in the production of PRRSV vaccines. Moreover, subsequent in vivo inoculation and challenge experiments demonstrated that rGD-SX-5U2 confers cross-protection against both HP-PRRSV and NADC30-like PRRSV, including an improvement in ADG levels and a reduction in viremia and lung tissue lesions. In conclusion, our research demonstrated that the chimeric PRRSV strain rGD-SX-5U2 is a novel approach that can provide broad-spectrum protection against both HP-PRRSV and NADC30-like PRRSV. This may be a significant improvement over previous MLV vaccinations.

► PRRS is a devastating disease of pigs despite availability of vaccines since 1994. ► Mechanisms of protective immunity are poorly understood. ► Correlates of immune protection are not known. ► Viral diversity complicates disease control and research interpretations. ► Understanding the limitations will help improve research efforts. Vaccination is the principal means used to control and treat porcine reproductive and respiratory syndrome virus (PRRSV) infection. An array of PRRS vaccine products is available in various regions of the world. However, despite extensive efforts, little progress has been made to improve efficacy since the first introduction of a live, attenuated vaccine in 1994 in the USA. Key limitations include: (a) uncertainty about the viral targets of protective immunity that prevents a research focus on individual viral structures and proteins, and frustrates efforts to design novel vaccines; (b) inability to establish clear immunological correlates of protection that requires laborious in vivo challenge models for evaluation of protection against challenge; and (c) the great genetic diversity of PRRSV which requires that challenge experiments be interpreted cautiously since it is not possible to predict how immunological protection against one isolate will translate to broadly cross-protective immunity. Economically significant levels of cross-protection that are provided to a variety of field isolates still cannot assure that effective protection will be conferred to isolates that might emerge in the future. In addition to these substantial barriers to new PRRSV vaccine development, there are enormous gaps in our understanding of porcine immunological mechanisms and processes that provide immunity to PRRSV infection and memory responses for long-term protection. Despite these impediments, we should be confident that progress will be made. Sequencing of the swine genome is providing a rich source of primary knowledge of gene structure and transcriptional regulation that is certain to reveal important insights about the mechanisms of anti-PRRSV immunity, and continued efforts to unravel the details of the interaction of PRRSV with pigs will lead to new insights that overcome the current limitations in the field.

Atypical porcine reproductive and respiratory syndrome (PRRS), which is caused by the Chinese highly pathogenic PRRS virus (HP-PRRSV), has resulted in large economic loss to the swine industry since its outbreak in 2006. However, to date, the region(s) within the viral genome that are related to the fatal virulence of HP-PRRSV remain unknown. In the present study, we generated a series of full-length infectious cDNA clones with swapped coding regions between the highly pathogenic RvJXwn and low pathogenic RvHB-1/3.9. Next, the in vitro and in vivo replication and pathogenicity for piglets of the rescued chimeric viruses were systematically analyzed and compared with their backbone viruses. First, we swapped the regions including the 5'UTR+ORF1a, ORF1b, and structural proteins (SPs)-coding region between the two viruses and demonstrated that the nonstructural protein-coding region, ORF1b, is directly related to the fatal virulence and increased replication efficiency of HP-PRRSV both in vitro and in vivo. Furthermore, we substituted the nonstructural protein (Nsp) 9-, Nsp10-, Nsp11- and Nsp12-coding regions separately; or Nsp9- and Nsp10-coding regions together; or Nsp9-, Nsp10- and Nsp11-coding regions simultaneously between the two viruses. Our results indicated that the HP-PRRSV Nsp9- and Nsp10-coding regions together are closely related to the replication efficiency in vitro and in vivo and are related to the increased pathogenicity and fatal virulence for piglets. Our findings suggest that Nsp9 and Nsp10 together contribute to the fatal virulence of HP-PRRSV emerging in China, helping to elucidate the pathogenesis of this virus.

Porcine reproductive and respiratory syndrome (PRRS) is considered to be one of the most costly diseases affecting intensive pig production worldwide. Control of PRRS is a complex issue and involves a combination of measures including monitoring, diagnosis, biosecurity, herd management, and immunization. In spite of the numerous studies dealing with PRRS virus epidemiology, transmission of the infection is still not fully understood. The present article reviews the current knowledge on PRRSV transmission between and within farm, and the impact of vaccination on virus transmission.

Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses in the global swine industry due to its high genetic diversity and different virulence levels, which complicate disease management and vaccine development. This study evaluated longitudinal changes in the immune cell composition of bronchoalveolar lavage fluid and the clinical outcomes across PRRSV strains with varying virulence, using techniques including single-cell transcriptomics. In highly virulent infection, faster viral replication results in an earlier peak lung-damage time point, marked by significant interstitial pneumonia, a significant decrease in macrophages, and an influx of lymphocytes. Viral tracking reveals less than 5% of macrophages are directly infected, and further analysis indicates bystander cell death, likely regulated by exosomal microRNAs as a significant factor. In contrast, the peak intermediate infection shows a delayed lung-damage time point with fewer cell population modifications. Furthermore, anti-inflammatory M2-like macrophages (SPP1-CXCL14 high ) are identified and their counts increase during the peak lung-damage time point, likely contributing to local defense and lung recovery, which is not observed in high virulent infection. These findings provide a comprehensive description of the immune cellular landscape and differential PRRSV virulence mechanisms, which will help build new hypotheses to understand PRRSV pathogenesis and other respiratory infections. Porcine reproductive and respiratory syndrome virus strains can have markedly different virulence in pigs. Here, the authors describe differences in the immune response to infection with varying virulence and suggest that M2-like macrophages may aid in recovery and lung health.

The pulmonary endothelium is a dynamic and metabolically active monolayer of endothelial cells. Dysfunction of the pulmonary endothelial barrier plays a crucial role in the acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), frequently observed in the context of viral pneumonia. Dysregulation of tight junction proteins can lead to the disruption of the endothelial barrier and subsequent leakage. Here, the highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) served as an ideal model for studying ALI and ARDS. The alveolar lavage fluid of pigs infected with HP-PRRSV, and the supernatant of HP-PRRSV infected pulmonary alveolar macrophages were respectively collected to treat the pulmonary microvascular endothelial cells (PMVECs) in Transwell culture system to explore the mechanism of pulmonary microvascular endothelial barrier leakage caused by viral infection. Cytokine screening, addition and blocking experiments revealed that proinflammatory cytokines IL-1β and TNF-α, secreted by HP-PRRSV-infected macrophages, disrupt the pulmonary microvascular endothelial barrier by downregulating claudin-8 and upregulating claudin-4 synergistically. Additionally, three transcription factors interleukin enhancer binding factor 2 (ILF2), general transcription factor III C subunit 2 (GTF3C2), and thyroid hormone receptor-associated protein 3 (THRAP3), were identified to accumulate in the nucleus of PMVECs, regulating the transcription of claudin-8 and claudin-4. Meanwhile, the upregulation of ssc-miR-185 was found to suppress claudin-8 expression via post-transcriptional inhibition. This study not only reveals the molecular mechanisms by which HP-PRRSV infection causes endothelial barrier leakage in acute lung injury, but also provides novel insights into the function and regulation of tight junctions in vascular homeostasis.

Background Previously, we identified a major quantitative trait locus (QTL) for host response to Porcine Respiratory and Reproductive Syndrome virus (PRRSV) infection in high linkage disequilibrium (LD) with SNP rs80800372 on Sus scrofa chromosome 4 (SSC4). Results Within this QTL, guanylate binding protein 5 ( GBP5 ) was differentially expressed (DE) (p < 0.05) in blood from AA versus AB rs80800372 genotyped pigs at 7,11, and 14 days post PRRSV infection. All variants within the GBP5 transcript in LD with rs80800372 exhibited allele specific expression (ASE) in AB individuals (p < 0.0001). A transcript re-assembly revealed three alternatively spliced transcripts for GBP5 . An intronic SNP in GBP5 , rs340943904, introduces a splice acceptor site that inserts five nucleotides into the transcript. Individuals homozygous for the unfavorable AA genotype predominantly produced this transcript, with a shifted reading frame and early stop codon that truncates the 88 C-terminal amino acids of the protein. RNA-seq analysis confirmed this SNP was associated with differential splicing by QTL genotype (p < 0.0001) and this was validated by quantitative capillary electrophoresis (p < 0.0001). The wild-type transcript was expressed at a higher level in AB versus AA individuals, whereas the five-nucleotide insertion transcript was the dominant form in AA individuals. Splicing and ASE results are consistent with the observed dominant nature of the favorable QTL allele. The rs340943904 SNP was also 100 % concordant with rs80800372 in a validation population that possessed an alternate form of the favorable B QTL haplotype. Conclusions GBP5 is known to play a role in inflammasome assembly during immune response. However, the role of GBP5 host genetic variation in viral immunity is novel. These findings demonstrate that rs340943904 is a strong candidate causal mutation for the SSC4 QTL that controls variation in host response to PRRSV.