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PEDV Discontinuous Transcription Generates A Novel Subgenomic RNA to Enhance Immune Evasion and Viral Fitness

ABSTRACT: During viral evolution, RNA viruses accumulate advantageous mutations that enhance replicative, adaptability, and evasion of host immune responses. While most studies have focused on amino acid substitutions that alter protein function, functional RNA-level mutations remain largely underexplored. In this study, we employed RNA-seq and Ribo-seq for the first time to analyze viral gene expression during replication of the porcine epidemic diarrhea virus (PEDV). We identified a novel subgenomic RNA (sgRNA) that encodes a truncated nucleocapsid isoform, designated N1. Evolutionary analysis revealed that a double-point mutation within the GII-b subclade facilitated the emergence of a functional transcriptional regulatory sequence (TRS-B) and a translation initiation codon. N1 promotes viral replication but is unable to substitute for the full-length N protein in the assembly of infectious virions. Mechanistically, N1 binds double-stranded RNA (dsRNA) and suppresses dsRNA-induced phosphorylation of protein kinase R (PKR) and eukaryotic translation initiation factor 2α (eIF2α), thereby inhibiting the formation of host stress granules (SG). Mutations at residues R133 and R134 markedly impair the dsRNA-binding capacity of N1 and its ability to inhibit SG formation. Further transcriptomic analysis of infected cells revealed that the absence of N1 enhances activation of host innate immune response following viral infection, thereby suppressing viral replication. Our findings demonstrate that PEDV can promote the generation of novel innate immune antagonists through the evolution of TRS-B, thereby enhancing its immune evasion ability and adaptation to the host.

ORGANISM(S): Porcine epidemic diarrhea virus

PROVIDER: GSE330067 | GEO | 2026/05/11

REPOSITORIES: GEO

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PEDV Discontinuous Transcription Generates A Novel Subgenomic RNA to Enhance Immune Evasion and Viral Fitness

Project description:During viral evolution, RNA viruses accumulate advantageous mutations that enhance replicative, adaptability, and evasion of host immune responses. While most studies have focused on amino acid substitutions that alter protein function, functional RNA-level mutations remain largely underexplored. In this study, we employed RNA-seq and Ribo-seq for the first time to analyze viral gene expression during replication of the porcine epidemic diarrhea virus (PEDV). We identified a novel subgenomic RNA (sgRNA) that encodes a truncated nucleocapsid isoform, designated N1. Evolutionary analysis revealed that a double-point mutation within the GII-b subclade facilitated the emergence of a functional transcriptional regulatory sequence (TRS-B) and a translation initiation codon. N1 promotes viral replication but is unable to substitute for the full-length N protein in the assembly of infectious virions. Mechanistically, N1 binds double-stranded RNA (dsRNA) and suppresses dsRNA-induced phosphorylation of protein kinase R (PKR) and eukaryotic translation initiation factor 2α (eIF2α), thereby inhibiting the formation of host stress granules (SG). Mutations at residues R133 and R134 markedly impair the dsRNA-binding capacity of N1 and its ability to inhibit SG formation. Further transcriptomic analysis of infected cells revealed that the absence of N1 enhances activation of host innate immune response following viral infection, thereby suppressing viral replication. Our findings demonstrate that PEDV can promote the generation of novel innate immune antagonists through the evolution of TRS-B, thereby enhancing its immune evasion ability and adaptation to the host.

2026-05-12 | GSE330201 | GEO

Coronavirus replication is controlled by both host and viral RNA m6A methylations

Project description:N6–methyladenosine (m6A) is the most abundant internal mRNA modification in eukaryotes, and it plays an important role in RNA metabolism and function. Recent studies have revealed that viral RNA m6A modification can play an anti-viral or pro-viral role in virus life cycle. However, whether m6A methylation can modulate replication of coronaviruses, which contain the largest known RNA genomes, remains elusive. Here, we determined that m6A modifications of porcine epidemic diarrhea coronavirus (PEDV) are exclusively located in the N gene at the 3’-end of genome, and that PEDV infection alters the expression pattern of host proteins involved in m6A modification. Depletion of m6A demethylases significantly increased PEDV replication and gene expression whereas knockdown of m6A methyltransferases slightly decreased PEDV infection. Interestingly, m6A binding proteins YTHDF 2 and 3 significantly inhibited PEDV replication whereas YTHDF1 has an opposite effect. When the major m6A sites in the N gene were mutated, the resultant recombinant PEDVs and PEDV replicons had a significant increase in replication and gene expression. This study illustrates that (i) addition of m6A to PEDV RNA inhibits viral replication, and (ii) both host and viral m6A machinery regulates coronavirus replication.

2022-12-01 | GSE141291 | GEO

Coronavirus replication is regulated by both host and viral RNA N6–methyladenosine modifications

Project description:N6–methyladenosine (m6A) is the most abundant internal mRNA modification in eukaryotes, and it plays an important role in RNA metabolism and function. Recent studies have revealed that viral RNA m6A modification can play an anti-viral or pro-viral role depending on the virus. However, whether m6A methylation can modulate replication of coronaviruses, which cause some severe human and animal diseases such as Coronavirus Disease 2019 (COVID-19), remains unknown. Here, we determined that m6A modifications of porcine epidemic diarrhea coronavirus (PEDV) are exclusively located in the N gene at the 3’-end of the genome, and that PEDV infection alters the expression pattern of some host proteins involved in m6A modification. Depletion of m6A demethylases significantly increased PEDV replication and gene expression whereas knockdown of m6A methyltransferases slightly decreased PEDV infection. Interestingly, m6A binding proteins YTHDF 2 and 3 significantly inhibited PEDV replication whereas YTHDF1 has the opposite effect. When the major m6A sites in the N gene were mutated, the resultant recombinant PEDVs and PEDV replicons had a significant increase in replication and gene expression. This study illustrates that (i) addition of m6A to PEDV RNA inhibits viral replication, and (ii) both host and viral m6A machinery regulate coronavirus replication.

2020-05-22 | GSE151020 | GEO

Unraveling the battle between a highly virulent PEDV strain and the host via single-cell transcriptomic analysis

Project description:Porcine epidemic diarrhea virus (PEDV) causes severe intestinal damage and high mortality in neonatal piglets. The continuous emergence of new strains has brought new challenges to prevention and control. In this study, we isolated and characterized a prevalent PEDV virulent strain, and analyzed 19,612 jejunal cells from PEDV-infected and control piglets using single-cell sequencing, revealing significant changes in cellular composition, gene expression, and intercellular communication. In response to PEDV infection, epithelial repair was enhanced through increased proliferation and differentiation of stem cells, transit-amplifying (TA) cells, and intestinal progenitor cells into enterocytes. Additionally, PEDV disrupted intercellular communication, compromising epithelial functionality while triggering immune responses, with IFN-II and IL-10 signaling activation acting as critical regulators of immune balance and tissue homeostasis. Beyond enterocytes, viral genes were detected in various other cell types. Further experiments confirmed that PEDV could initiate replication in B and T lymphocytes but was unable to produce infectious progeny, with T cells additionally undergoing virus-induced apoptosis. These findings provide new insights into PEDV tropism, immune evasion, and epithelial repair, revealing complex host-pathogen interactions that shape disease progression and tissue regeneration, thereby contributing to a better understanding of enteric coronavirus pathogenesis.

2025-04-22 | GSE293713 | GEO

A recombination-resistant genome for live attenuated and stable PEDV vaccines by engineering the transcriptional regulatory sequences

Project description:Porcine epidemic diarrhea virus (PEDV) is a deadly coronavirus for neonatal piglets and no effective vaccines are available. Transcriptional regulatory sequences (TRSs) are critical in regulating coronavirus discontinuous transcription. Also, TRSs contribute to a high recombination rate of coronaviruses, leading to difficulty in developing safe live vaccines. We hypothesize that recoding the TRS core sequences (TRS-CS) of PEDV can make the recombination impossible between the engineered vaccine virus and field strains or wildtype viruses. We used an infectious clone-derived reporter PEDV, dORF3-EGFP, as the backbone to generate a remodeled TRS (RMT) mutant that carries the recoded leader and body TRS-CSs. The RMT and dORF3-EGFP showed comparable replication efficiency in Vero cells. However, the incompatibility between the rewired and wildtype TRS-CSs led to few EGFP in RMT-infected cells. Furthermore, RMT and dORF3-EGFP had a similar attenuated phenotype, replication efficiency, and protective immunogenicity in neonatal pigs. RNA sequencing analysis indicated that EGFP transcription directed by the heterogenous TRS-CSs was significantly reduced to an extremely low level. Meanwhile, recombinant viruses were not detected in Vero cells and in pigs that were co-infected with RMT and a PEDV S-INDEL strain, Iowa106. In vitro and in vivo passaging of the RMT did not result in reversion mutations in the rewired TRS-CSs, introduced gaps, and disrupted wildtype TRSs. In summary, the RMT mutant was resistant to recombination and genetically stable and can be further optimized (e.g., deletion of the EGFP) to serve as a platform to develop safe PEDV live attenuated vaccines.

2023-11-04 | GSE246991 | GEO

Deciphering how viral epitranscriptome shapes host immune response 1

Project description:As early as 24 hours after RNA virus infection, up to 25% of all RNA molecules present in host cells are pathogenic viral RNA (vRNA), i.e. viral messenger RNA (vmRNA), viral genomic RNA (vgRNA), and double stranded replication intermediates (dsRNA). To prevent such a takeover of the host metabolism, the innate immune system of the infected organism must detect threat as soon as possible. When considering RNA viruses recognition, activation of timely proper immune response capable of sensing and neutralizing viral genetic material is crucial for cell survival. Viral nucleic acids are one of the strongest pathogen-associated molecular patterns (PAMPs), molecules causing particular immune system reactions. Human cells are armed with a variety of pattern recognition receptors (PRRs) responsible for PAMPs recognition. The main factors responsible for detecting foreign nucleic acids in mammalian cells have already been identified. For activation of any RNA sensor, detecting an abnormal molecular RNA pattern, not present under normal conditions, is obligatory. These patterns may be some chemical modification of RNA, or the absence of such one, specific secondary or tertiary RNA structure, particular sequence, or dsRNA that can derive from viral genome as it is in the case of dsRNA viruses or from annealed complementary RNA strands, which are generated as RNA virus replication intermediates. However, yet there is still very limited understanding of how different epitranscriptomic marks modulate host immune response. Therefore, we will attempt to comprehensively understand how chemical modifications of viral RNA influence its immunogenic potential and stability in infected cells. Moreover, we will study how epitranscriptomic marks deposited on viral RNAs shield transcripts from being recognized by host antiviral factors.

2025-03-17 | PXD043620 | Pride

SARS-CoV-2 nsp14 induces the m7G methylation and the sequestration of host RNAs in stress granules Twin-Strep Streptactin pull-down LC-MSMS

Project description:Viruses grab the host translation machinery to facilitate their replication by disturbing the host translation. SARS-CoV-2 nsp14 was known to inhibit host translation, yet the mechanistic details are still obscure. In this study, we report that nsp14 can elevate stress granules (SG) formation in a N7 methyltransferase activity-dependent manner. ER/Golgi localized nsp14 promotes m7G methylation of host RNAs, which are delivered into stress granules (SG), leading to elevated SG formation. Except for a few methylation-associated proteins, most components of SGs induced by nsp14 can be identified in SGs induced by other stress inducers, like sodium arsenite. nsp14-induced SG formation relies on methyl donors, because altering the amount of methyl donors, like decreasing SAM level with overexpression of Glycine N-methyltransferase (GNMT) or increasing SAM level with the supplement of folic acid, can alter SG formation and affect viral replication. Collectively, we characterized nsp14 as an SG formation regulator involved in viral hijacking of the host translation machinery.

2026-02-06 | PXD060757 | Pride

SARS-CoV-2 nsp14 induces the m7G methylation and the sequestration of host RNAs in stress granules TurboID Biotin-Streptavidin pull-down LC-MSMS

2026-02-06 | PXD060759 | Pride

Determination of dsRNA interactome upon Sindbis virus infection in human cells identifies SFPQ as a critical proviral factor

Project description:Viruses are obligate intracellular parasites, which depend on the host cellular machineries to replicate their genome and complete their infectious cycle. Long double stranded (ds)RNA is a common viral by-product originating during RNA virus replication, which is universally sensed as a danger signal to trigger the antiviral response. As a result, viruses hide dsRNA intermediates into viral replication factories and have evolved strategies to hijack cellular proteins for their benefit. The characterization of the host factors associated to viral dsRNA and involved in viral replication remains a major challenge to develop new antiviral drugs against RNA viruses. Here, we performed anti-dsRNA immunoprecipitation followed by Mass Spectrometry to fully characterize the dsRNA interactome in Sindbis virus (SINV) infected human HCT116 cells. Among the validated factors, we characterized SFPQ (Splicing factor, proline-glutamine rich) as a new dsRNA-associated factor upon SINV infection. We proved that SFPQ is able to directly bind dsRNAs in vitro, that SFPQ association to dsRNA is independent on single-stranded (ss)RNA flanking regions in vivo and that it is able to bind the viral genome upon infection. Furthermore, we showed that either knock-down or knock-out of SFPQ reduced SINV infection in human HCT116 and SKNBE cells, suggesting that SFPQ could enhance viral replication. Overall, this study not only represents a resource to further study SINV dsRNA-associated factors upon infection but also identifies SFPQ as a new proviral dsRNA binding protein.

2024-05-22 | PXD024554 | Pride

Porcine epidemic diarrhea virus manipulates IMPDH-dependent nucleotide biosynthesis to facilitate replication

Project description:<p>Porcine epidemic diarrhea virus (PEDV) causes acute intestinal disease in pigs and remains a major threat to the global swine industry due to its high morbidity and mortality in neonatal piglets. To investigate host metabolic alterations upon PEDV infection, we performed untargeted metabolomic profiling in LLC-PK1 and Vero E6 cells. Pathway enrichment analysis revealed significant changes in nucleotide metabolism, cofactor biosynthesis, amino acid biosynthesis, and purine metabolism. Notably, PEDV infection led to divergent regulation of purine metabolism in the two cell types—upregulation in Vero E6 cells and downregulation in LLC-PK1 cells at 18 hours post-infection. We further identified inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in guanine nucleotide biosynthesis, as a critical host factor for PEDV replication. Both genetic knockdown of IMPDH2 and pharmacological inhibition using merimepodib (VX-497, MMPD) significantly reduced viral RNA levels and impaired replication. These treatments also suppressed host nucleotide biosynthetic activity. Together, our findings demonstrate that PEDV hijacks the IMPDH-dependent guanosine biosynthesis pathway to support its replication, and identify IMPDH as a promising host-directed antiviral target against PEDV.</p>

2025-10-17 | MTBLS13153 | MetaboLights

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