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PubMed2026

EscaPRRS-ORF5: a structure-aware evolutionary framework for prioritizing immune escape-prone variants in porcine reproductive and respiratory syndrome virus.

MOTIVATION: Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is a rapidly evolving RNA virus causing significant economic losses, posing a formidable challenge to vaccine efficacy due to its high mutational variability and immune escape. As the viral mutants evolve, their ability to sustain in population is driven by a range of host biology factors such as receptor binding, fusion, and uncoating. Existing tools that predict viral fitness and escape propensities rely heavily on extensive, up-to-date sequence data and lack integration of biochemical host interactions, limiting mechanistic understanding of the mutational landscape. We introduce Esca, a sequence-only toolchain framework that identifies immune escape-prone residues by exhaustively scanning each residue position for all amino acid substitutions using a Bayesian Variational Autoencoder (VAE) trained on protein language model embeddings. We demonstrate Esca on the GP5(ORF5) glycoprotein of PRRSV (EscaPRRS-ORF5) by training on ESM-2 embeddings of 32 146 GP5 sequences (2015-2022) spanning 140 sub-lineages. RESULTS: Despite being trained only on GP5 sequence data, EscaPRRS-ORF5 recovered 85.7% of the surface-exposed receptor binding interfaces as escape-prone regions. We use a mutation-sensitive fitness scoring scheme that goes beyond Hamming distances, to predict antibody escape tendencies, supporting surveillance of (re) emerging PRRSV variants. We do not claim that ORF5 alone captures PRRSV evolution or serves as a surveillance endpoint; rather, Esca offers a scalable path toward whole-genome, structure-aware surveillance. AVAILABILITY AND IMPLEMENTATION: EscaPRRS-ORF5 is freely available at https://doi.org/10.6084/m9.figshare.32661033 with an interactive Colab notebook at https://colab.research.google.com/drive/1TEgzAhPwvNAZ01VXeJbIFibfri2jnDA5? usp=sharing.

Porcine respiratory and reproductive syndrome viru↗

PubMed2013

Broadening the heterologous cross-neutralizing antibody inducing ability of porcine reproductive and respiratory syndrome virus by breeding the GP4 or M genes.

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important swine pathogens, which causes reproductive failure in sows and respiratory disease in piglets. A major hurdle to control PRRSV is the ineffectiveness of the current vaccines to confer protection against heterologous strains. Since both GP4 and M genes of PRRSV induce neutralizing antibodies, in this study we molecularly bred PRRSV through DNA shuffling of the GP4 and M genes, separately, from six genetically different strains of PRRSV in an attempt to identify chimeras with improved heterologous cross-neutralizing capability. The shuffled GP4 and M genes libraries were each cloned into the backbone of PRRSV strain VR2385 infectious clone pIR-VR2385-CA. Three GP4-shuffled chimeras and five M-shuffled chimeras, each representing sequences from all six parental strains, were selected and further characterized in vitro and in pigs. These eight chimeric viruses showed similar levels of replication with their backbone strain VR2385 both in vitro and in vivo, indicating that the DNA shuffling of GP4 and M genes did not significantly impair the replication ability of these chimeras. Cross-neutralization test revealed that the GP4-shuffled chimera GP4TS14 induced significantly higher cross-neutralizing antibodies against heterologous strains FL-12 and NADC20, and similarly that the M-shuffled chimera MTS57 also induced significantly higher levels of cross-neutralizing antibodies against heterologous strains MN184B and NADC20, when compared with their backbone parental strain VR2385 in infected pigs. The results suggest that DNA shuffling of the GP4 or M genes from different parental viruses can broaden the cross-neutralizing antibody-inducing ability of the chimeric viruses against heterologous PRRSV strains. The study has important implications for future development of a broadly protective vaccine against PRRSV.

Animals↗

PubMed2026

Repeated Cross-Sectional Surveillance and ORF5-Based Molecular Epidemiology of Porcine Reproductive and Respiratory Syndrome Virus in Anhui Province, China, 2019-2024.

Porcine reproductive and respiratory syndrome virus (PRRSV) remains a major threat to swine production, and its circulation after the African swine fever outbreak requires continued surveillance. This study investigated the temporal, regional, and genetic characteristics of PRRSV in Anhui Province from September 2019 to November 2024. Ten rounds of repeated cross-sectional surveillance were conducted at 147 slaughterhouses and 21 rendering plants. Tissue samples were collected by random, cluster, or risk-based sampling, pooled in groups of five, and tested by RT-qPCR. Representative positive samples with Ct values < 25 underwent ORF5 amplification, Sanger sequencing, and phylogenetic analysis. A total of 994 site visits yielded 18,733 tissue samples. No positive samples were detected in autumn 2020 or spring 2021, whereas PRRSV was detected again from autumn 2021 and subsequently fluctuated. The highest site-level positivity was 41.18% in autumn 2023, and the highest estimated individual-level positivity was 4.66% in spring 2023. Regional differences were statistically significant, with the highest site-level positivity in northern Anhui, and pooled-sample positivity was higher in rendering plants than in slaughterhouses. All 24 ORF5 sequences belonged to PRRSV-2 and mainly clustered with NADC30-like, NADC34-like, or MLV/classical strains. These findings demonstrate temporal fluctuations and lineage coexistence, supporting continued multisource surveillance and broader genomic and antigenic evaluation.

NADC30-like↗

PubMed2026

A CRISPR-Cas9 screen identifies LAPTM4A (lysosomal protein transmembrane 4 alpha) as a key host barrier against PRRSV infection.

Porcine reproductive and respiratory syndrome virus (PRRSV) manipulates host intracellular processes, particularly macroautophagy/autophagy and lysosomal function, to facilitate its replication and spread. However, the precise host factors and molecular mechanisms by which PRRSV remodels the autophagy-lysosome axis remain poorly defined. Here, we performed a CRISPR-Cas9 knockout screen targeting 1,332 genes involved in protein degradation, metabolism, and vesicular trafficking, and identified LAPTM4A (lysosomal protein transmembrane 4 alpha) as a critical antiviral factor involved in the lysosomal pathway. A yeast two-hybrid screen identified LAPTM4A as an interactor of PRRSV GP5 (glycoprotein 5). Mechanistically, GP5 recruits the E3 ubiquitin ligase NEDD4 and the autophagy receptor SQSTM1/p62 to promote K63-linked polyubiquitination of LAPTM4A, leading to its autophagic degradation. This selective degradation activates the AMPK-ULK1-MAP1LC3/LC3 signaling cascade, initiating autophagy while facilitating MTOR-lysosome colocalization, thereby suppressing TFEB nuclear translocation and transcription of lysosome-related genes. The resulting incomplete autophagic flux enhances viral replication. Additionally, in terms of host defense, LAPTM4A maintains lysosomal homeostasis by restraining excessive autophagy through AMPK-ULK1-LC3 signaling and promoting TFEB-dependent lysosomal gene expression by impairing the binding of RPTOR/raptor to MTOR, thus providing broad antiviral protection against multiple RNA viruses. Collectively, our findings identify LAPTM4A as a central regulator of lysosome-autophagy homeostasis and reveal a viral strategy that dismantles this defense axis to facilitate infection.Abbreviations: ATG5: autophagy related 5; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; Baf A1: bafilomycin A1; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DMVT library: protein degradation, metabolism, and vesicular trafficking library; LAPTM4A: lysosomal protein transmembrane 4 alpha; MAGeCK: model-based analysis of genome-wide CRISPR-Cas9 knockout; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NC: negative control; PAMs: porcine alveolar macrophages; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PRRSV: porcine reproductive and respiratory syndrome virus; qRT-PCR: quantitative real-time PCR; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TCID50: 50% tissue culture infective dose; TFEB: transcription factor EB; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type.

Animals↗

PubMed2026

Quercetin, a flavonoid, suppresses viral proliferation by interfering with the ubiquitin transfer from E1 to E2 enzymes.

Quercetin is recognized for diverse pharmacological activities. However, the mechanism underlying its broad-antiviral effects has not been elucidated. Herein, we identified quercetin as a potent inhibitor of both double-stranded DNA virus Bombyx mori nucleopolyhedrovirus (BmNPV) and single-stranded RNA virus porcine reproductive and respiratory syndrome virus (PRRSV). Surface plasmon resonance (SPR) revealed that quercetin targets host ubiquitin-activating enzyme 1 (Uba1) homologs. Uba1 knockdown reduced viral proliferation and enhanced the antiviral effect of quercetin, whereas Uba1 overexpression functioned oppositely. Quercetin bound Uba1 homologs with high affinity. Notably, mutation of two binding residues, Q977 and G978, significantly disrupted the binding between BmUba1 and quercetin, and abolished quercetin's antiviral activity. Quercetin obstructed the transfer of ubiquitin from Uba1 to the E2 enzyme Ubc6, impairing the ubiquitination process. Similarly, quercetin inhibited PRRSV proliferation via targeting Uba1 in mammals. These findings elucidate the molecular mechanism underlying the pharmacological effects of quercetin, providing a theoretical basis for the development of novel antiviral agents against both DNA and RNA viruses.

Quercetin↗

PubMed2026

PRRSV suppresses FTO-dependent m6A demethylation to reprogram STAT signaling and innate immunity.

RNA viruses have evolved diverse strategies to evade host interferon (IFN)-stimulated gene (ISG) defenses; however, how they exploit host epitranscriptomic regulation remains poorly understood. Here, we identify an immune-evasion mechanism in which porcine reproductive and respiratory syndrome virus (PRRSV) targets the m6A demethylase fat mass and obesity-associated protein (FTO) to suppress antiviral signaling. Mechanistically, the viral endoribonuclease nsp11 inhibits STAT5-dependent transcription through the key residues Q96 and S104, thereby reducing FTO expression. Loss of FTO increases m6A modification of STAT2 and STAT3 transcripts, impairing their translation and phosphorylation, thereby attenuating ISG responses. Reduced STAT3 activity further dampens STAT5 signaling, establishing a feed-forward circuit that amplifies suppression of antiviral immunity. Functionally, disruption of this regulatory region (Q96A and S104A) attenuates viral pathogenicity in vivo and restores ISG induction. These mutations also reduce infection-associated inflammatory responses and the accumulation of reactive oxygen species. Together, these findings define a nsp11-STAT5-FTO-STAT2/3 axis that enables PRRSV to reprogram host epitranscriptomic control of innate immunity. Our work reveals a mechanism of epitranscriptomic hijacking and identifies FTO as a key host factor exploited by RNA viruses, highlighting m6A regulation as a potential target for antiviral intervention.IMPORTANCEViruses must overcome host innate immune defenses to establish infection; however, the mechanisms by which they manipulate host RNA regulation remain incompletely understood. In this study, we show that porcine reproductive and respiratory syndrome virus (PRRSV) suppresses interferon responses by targeting the host m6A demethylase FTO through its endoribonuclease nsp11. This process involves the inhibition of STAT5 phosphorylation, which reduces FTO expression and increases m6A modification of key immune regulators, including STAT2 and STAT3, thereby impairing their activation. Disruption of this pathway attenuates viral pathogenicity in vivo and restores antiviral signaling. These results demonstrate that PRRSV can reprogram host epitranscriptomic regulation to modulate innate immunity and suggest that m6A-related pathways may be potential targets for antiviral intervention.

Immunity, Innate↗

PubMed2026

A descriptive analysis of Streptococcus suis-associated disease in Irish pigs from 2010 to 2024: serotypes, pathology, and antimicrobial resistance.

BACKGROUND: Streptococcus suis is a major cause of respiratory and systemic diseases in post-weaned pigs, leading to significant production losses and animal welfare concerns. This study provides the first long-term national level analysis of Streptococcus suis-associated disease (SSAD) in the Republic of Ireland. We examined the pig diagnostic submissions, characterised serotype distribution, antimicrobial susceptibility, and co-infection patterns from 2010 to 2024. RESULTS: The findings confirm that serotypes 9 and 2 or 1/2 were most frequently associated with disease. We observed a significant shift in recent years where serotype 9 has surpassed serotype 2 or 1/2 in number of occurrences. S. suis was frequently co-detected with viral pathogens including porcine reproductive and respiratory syndrome virus (PRRSV), porcine circovirus type 2, and swine influenza virus (SIV), as well as bacterial pathogens such as Actinobacillus pleuropneumonia and Pasteurella multocida, typically from pneumonic lungs. While resistance to tetracycline and erythromycin was high (44.4% to 65.8%), isolates remained susceptible to first-line beta-lactam antibiotics such as penicillin (7.9% resistance), ampicillin (5.5% resistance) and amoxycillin/clavulanate (0% resistance). CONCLUSION: The observed heterogeneity between and within herds challenges successful implementation of vaccination and highlights the need for ongoing disease monitoring. These findings provide the first in-depth assessment of SSAD in Ireland's pig population which will offer valuable insights for future surveillance efforts, including genomic studies and supporting evidence-based strategies and vaccine selection for controlling S. suis in Irish pig sector.

Ireland↗

PubMed2026

Mössbauer spectroscopy in drug discovery: revealing Fe- and Fe-S cluster dependent targets.

INTRODUCTION: Iron- and iron-sulfur cluster (Fe-S)-containing proteins are essential for diverse biological processes, including electron transfer, genome maintenance, metabolism, cellular signaling, and host-pathogen interactions. Despite their broad biological importance and growing links to human disease, Fe-S cluster-dependent proteins remain underexplored as therapeutic targets, largely because it is difficult to define their metal-dependent chemistry using conventional biochemical, spectroscopic, and structural approaches. AREAS COVERED: This review examines how Mössbauer spectroscopy can be integrated into workflows for metalloprotein characterization, target validation, and drug discovery. Using representative Fe-S cluster-containing proteins, the practical considerations for implementing Mössbauer spectroscopy are outlined, including 57Fe-enriched expression, sample preparation, and spectroscopic analysis. Two case studies of experimentally challenging viral Fe-S cluster proteins are then highlighted, the Hepatitis B virus X protein and the Porcine Reproductive and Respiratory Syndrome Virus Nsp1α protease, which demonstrate how direct characterization of metal cofactors can reveal previously unrecognized therapeutic avenues. Relevant literature published through March 2026 was identified using PubMed and Google Scholar with keywords related to Mössbauer spectroscopy, iron-sulfur proteins, viral metalloproteins, and drug discovery. EXPERT OPINION: As drug discovery increasingly seeks to exploit metal-dependent biology, Mössbauer spectroscopy will play an important role in identifying cryptic metalloproteins, defining their native states, and uncovering Fe- and Fe-S cluster-dependent targets. Mössbauer spectroscopy can also be complementary, and integrated with structural and AI-driven approaches to answer emerging challenges in medicinal chemistry.

Humans↗