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Bovine viral diarrhoea (BVD) is one of the most economically damaging livestock enzootic diseases in the world. BVD aetiological agents are three pestiviruses (BVDV-1, -2 and HoBi-like pestivirus), which exhibit high genetic diversity and complex transmission cycles. This considerably hampers the management of the disease, which is why eradication plans have been implemented in several countries. In France, a national plan has been in place since 2019. Our understanding of its impact on the distribution of BVDV genotypes is limited by the availability of French genetic data. Here, we conducted a molecular epidemiology study to refine our knowledge of BVDV genetic diversity in France, characterise its international relationships, and analyse national spatio-temporal genotypic distribution. We collated 1037 BVDV-positive samples throughout France between 2011 and 2023, with a greater sampling effort in two major cattle production areas. We developed a high-throughput sequencing protocol which we used to complete the 5’UTR genotyping of this collection. We show that two main BVDV-1 genotypes, 1e and 1b, account for 88% of genotyped sequences. We also identified seven other BVDV-1 genotypes occurring at low frequencies and three BVDV-2 samples (genotype 2c). Phylogenetic analyses indicate different worldwide distribution patterns between the two main BVDV-1 genotypes. Their relative frequencies present no major changes in France since the 1990s and few variations at the national scale. We also found some degree of local spatial structuring in western France. Overall, our results demonstrate the potential of large-scale sequence-based surveillance to monitor changes in the epidemiological situation of enzootic diseases.

Bovine viral diarrhea virus (BVDV) belongs to the family Flaviviridae genus pestivirus. The viral genome is a single-stranded, positive-sense RNA that encodes four structural proteins (i.e., C, Erns, E1, and E2) and eight non-structural proteins (NSPs) (i.e., Npro, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). Cattle infected with BVDV exhibit a number of different clinical signs including diarrhea, abortion, and other reproductive disorders which have a serious impact on the cattle industry worldwide. Research on BVDV mainly focuses on its structural protein, however, progress in understanding the functions of the NSPs of BVDV has also been made in recent decades. The knowledge gained on the BVDV non-structural proteins is helpful to more fully understand the viral replication process and the molecular mechanism of viral persistent infection. This review focuses on the functions of BVDV NSPs and provides references for the identification of BVDV, the diagnosis and prevention of Bovine viral diarrhea mucosal disease (BVD-MD), and the development of vaccines.

Multivalent live-attenuated or inactivated vaccines are often used to control the bovine viral diarrhea disease (BVD). Still, they retain inherent disadvantages and do not provide the expected protection. This study developed a new vaccine prototype, including the external segment of the E2 viral protein from five different subgenotypes selected after a massive screening. The E2 proteins of every subgenotype (1aE2, 1bE2, 1cE2, 1dE2, and 1eE2) were produced in mammalian cells and purified by IMAC. An equimolar mixture of E2 proteins formulated in an oil-in-water adjuvant made up the vaccine candidate, inducing a high humoral response at 50, 100, and 150 µg doses in sheep. A similar immune response was observed in bovines at 50 µg. The cellular response showed a significant increase in the transcript levels of relevant Th1 cytokines, while those corresponding to the Th2 cytokine IL-4 and the negative control were similar. High levels of neutralizing antibodies against the subgenotype BVDV1a demonstrated the effectiveness of our vaccine candidate, similar to that observed in the sera of animals vaccinated with the commercial vaccine. These results suggest that our vaccine prototype could become an effective recombinant vaccine against the BVD.

Bovine viral diarrhea virus (BVDV) is a major pathogen affecting livestock health in China. However, the current epidemiological status in yaks ( ), particularly in Qinghai Province, remains insufficiently understood. In the present study, a comprehensive serological and molecular investigation of BVDV in yaks was conducted across broad geographic areas of eight administrative regions including Yushu, Guoluo, Huangnan, Hainan, Haidong, Haixi, Haibei, and Xining in Qinghai Province. The results revealed widespread BVDV exposure in Qinghai yak, with an overall antibody prevalence of 84.52% (1158/1370) and substantial herd variation (12.00~98.07%). Active infections were confirmed through antigen detection, revealing prevalence ranging from 0.34% (Haixi) to 4.90% (Huangnan). Genetic characterization identified two circulating subgenotypes: BVDV-1a (n=3) and the predominant BVDV-1u (n=30), with the latter dominating across all regions. These results highlight the endemic circulation of BVDV in Qinghai yak populations and uncover unexpected genetic diversity, emphasizing the need for control measures to mitigate the adverse impacts of BVDV infection in yaks in high-altitude pastoral systems.

Bovine pestiviruses are members of the species Pestivirus A (bovine viral diarrhea virus 1, BVDV-1), Pestivirus B (BVDV-2) or Pestivirus H (HoBiPeV). To date, BVDV-2 isolates/strains have been classified into three subtypes (a-c) by phylogenetic analysis, and an additional subtype (d) has been proposed based on 5' untranslated region (UTR) secondary structures. In a previous study, we identified some BVDV-2 sequences in the GenBank database that could not be classified as subtype a, b or c by phylogenetic analysis of their genomes, UTRs or individual genes. Here, we performed a detailed study of these sequences and assessed whether they might represent a distinct BVDV-2 subtype. Initially, we collected 85 BVDV-2 complete/near-complete genomes (CNCGs) from GenBank and performed a “proof of equivalence” between phylogenetic analyses based on CNCGs and open reading frames (ORFs), which showed that ORFs may be reliably used as a reference target for BVDV-2 phylogeny, allowing us to increase our dataset to 139 sequences. Among these, we found seven sequences that could not be classified as BVDV-2a-c. The same was observed in the phylogenetic analysis of CNCGs and viral genes. In addition, the seven non-BVDV-2a-c sequences formed a distinct cluster in all phylogenetic trees, which we propose to term BVDV-2e. BVDV-2e also showed 44 amino acid changes compared to BVDV-2a-c, 20 of which are in well-defined positions. Importantly, an additional phylogenetic analysis including BVDV-2d and a pairwise comparison of BVDV-2e and BVDV-2d sequences also supported the difference between these subtypes. Finally, we propose the recognition of BVDV-2e as a distinct BVDV-2 subtype and encourage its inclusion in future phylogenetic analyses to understand its distribution and evolution.

Background Bovine viral diarrhea virus (BVDV) is a pervasive respiratory pathogen of economic concern for the cattle industry. Transplacental infection results in abortion or the establishment of a tolerant and persistent viral infection. Deletion viral genomes (DelVGs) are naturally occurring products of the viral replication process. These deletion viral genomic transcripts are generated with truncations of various sizes that severely impede or prevent self-replication. DelVGs have been implicated in the establishment of viral persistence. Methods We used a bioinformatic pipeline to discover the presence of BVDV DelVGs. These DelVGs were identified via analysis of Illumina MiSeq reads from 74 BVDV1 field isolates from two closely related subgenotypes and from an  in vitro  passage of a BVDV1a virus at two different multiplicities of infection (MOI). Results After the identification of DelVGs, we assessed their phylogenetic linkage to begin elucidating potential roles in the viral life cycle and persistence. BVDV1a viruses queried generate significantly more DelVGs, with 52% of 5’ and 3’ junctions occurring in the core/capsid (C) region and a major NS2-NS5B deletion species. In contrast, the BVDV1b viruses generated significantly fewer DelVGs, especially a reduction in C region deletions. In vitro  passaging of the BVDV1a Singer virus demonstrated that MOI significantly impacts the generation of DelVGs, with higher MOIs generating more DelVGs and a different deletion profile. Conclusions Here, we report that the BVDV1a and BVDV1b subgenotypes generate diverse species of DelVGs. These DelVGs may play key roles in BVDV evolution and the establishment of persistence during transplacental infection.

In this communication, we report the presence of RNA of bovine viral diarrhea virus (BVDV) as a contaminant of different biological products used in Mexico for veterinary vaccine production. For this purpose, six batches of monovalent vaccines, eight cell line batches used for vaccine production, and 10 fetal bovine serum lots (FBS) commercially available in Mexico from different suppliers were tested by reverse transcription polymerase chain reaction (RT-PCR). Viral RNA was detected in 62.5% of the samples analyzed. Phylogenetic analysis revealed the presence of the subgenotypes BVDV-1a, 1b, and BVDV-2a in the tested samples. Collectively, these findings indicate that contamination by BVDV RNA occurs in commercial vaccines and reagents used in research and production of biological products. The ramifications of this contamination are discussed.

In 2019, diarrhea cases occurred on cattle farms in Qionglai and Guang'an, Sichuan Province. Two out of 20 (10%) serum and nasal swab samples were positive when tested using a bovine viral diarrhea virus (BVDV) antigen-capture ELISA kit. Two non-cytopathic strains of BVDV were isolated and named QL1903 and GA190608, respectively. The nucleotide sequences of the genomes of the two isolates were 89.52% identical. Phylogenetic analysis based on the 5'-UTR sequence revealed that the BVDV isolate QL1903 belonged to BVDV subtype 1b, whereas isolate GA190608 clustered with strains HN1814, EN-19, and BJ09_26 in a separate branch, which has tentatively been classified as a new genetic subtype, \"1v\".

•Virus neutralization (VN) titers are used for BVDV antigenic characterization.•Interpretation of large amounts of VN data can be challenging.•Principal Component Analysis (PCA) to approach VN results interpretation.•PCA generated a scatter plot with easy visualization of antigenic groups.•PCA can be a method to visualize BVDV antigenic relationships. Bovine viral diarrhea virus (BVDV) is comprised of two species, BVDV-1 and BVDV-2, but given the genetic diversity among pestiviruses, at least 21 subgenotypes are described for BVDV-1 and 4 for BVDV-2. Genetic characterization can be achieved through complete or partial sequencing and phylogeny, but antigenic characterization can be difficult to determine due to the antigenic diversity and cross-neutralization that exists among isolates. The traditional method for evaluating antigenic relationships between pestivirus isolates is the virus neutralization (VN) assay, but interpretation of the data to determine antigenic difference can be unclear. Data from this study utilized a multivariate analysis for visualization of VN results to analyze the antigenic relationships between vaccine strains and multiple field isolates. Polyclonal sera were generated against 6 BVDV strains currently contained in vaccine formulations, and each serum was used in VN’s to measure the neutralizing antibody titers against 15 BVDV field isolates characterized as prevalent and divergent subgenotypes in the USA. Principal component analysis (PCA) were performed on the VN assay datasets, and results were interpreted from PCA clustering within the PCA dendrogram and scatter plot. The results demonstrated clustering patterns among isolates suggestive of antigenic differences. While expected, the BVDV-1 and BVDV-2 isolates did not cluster together and had the greatest spatial distribution. In addition, other BVDV isolates had distinct spatial patterns suggesting antigenically divergent isolates. This analysis provides an alternative and more efficient means to analyze large VN datasets to visualize antigenic relationships between pestivirus isolates. This analysis could be beneficial for vaccine development and evaluation of efficacy, since most vaccines cannot fully protect animals from the broad range diversity of BVDV viruses.

MicroRNAs (miRNAs) are endogenous small and noncoding RNA molecules (18–25 nt) that can regulate expression of their target genes post-transcriptionally. Previously, using high-throughput sequencing data obtained on a Solexa platform, we found that Bos taurus bta-miR-2904 (miR-2904) was significantly upregulated in Madin–Darby bovine kidney (MDBK) cells infected with bovine viral diarrhea virus (BVDV) strain NADL at 2, 6, and 18 h postinfection (hpi) compared to uninfected MDBK cells. Moreover, miR-2904 overexpression significantly reduced BVDV replication. However, the mechanism by which miR-2904 inhibits viral replication remains unclear. In this study, we used electron microscopy, laser confocal microscopy, dual-luciferase reporter analysis, real-time PCR, and Western blot assays to investigate the effect of the miR-2904 expression on BVDV NADL replication and virus-infection-induced autophagy. The results indicate that miR-2904 inhibits autophagy of MDBK cells by targeting autophagy-related gene 13 (ATG13), and overexpression of miR-2904 inhibited the replication of BVDV NADL.