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Endogenous human herpesviruses 6A/B. 内源性人疱疹病毒6A/B。
IF 3.8 2区 医学
Journal of Virology Pub Date : 2025-08-01 DOI: 10.1128/jvi.01054-25
Louis Flamand, Jesse Arbuckle, Pascale Bonnafous, Vincent Descamps, Joshua A Hill, Ruth Jarrett, Keith Jerome, Benedikt B Kaufer, Rie Koide, Anthony L Komaroff, Peter Medveczky, Hiroki Miura, Yasuko Mori, Nicholas Parrish, Philip E Pellett, Michael Wood, Tetsushi Yoshikawa, Danielle M Zerr
{"title":"Endogenous human herpesviruses 6A/B.","authors":"Louis Flamand, Jesse Arbuckle, Pascale Bonnafous, Vincent Descamps, Joshua A Hill, Ruth Jarrett, Keith Jerome, Benedikt B Kaufer, Rie Koide, Anthony L Komaroff, Peter Medveczky, Hiroki Miura, Yasuko Mori, Nicholas Parrish, Philip E Pellett, Michael Wood, Tetsushi Yoshikawa, Danielle M Zerr","doi":"10.1128/jvi.01054-25","DOIUrl":"https://doi.org/10.1128/jvi.01054-25","url":null,"abstract":"<p><p>Human herpesviruses 6A and 6B (HHV-6A/B) can integrate into the germline, resulting in inherited viral DNA-now proposed to be called \"endogenous HHV-6A/B (eHHV-6A/B).\" Present in 0.2-3% of humans, this integrated DNA is passed to offspring and may reactivate, posing health risks such as angina or lupus. To reduce confusion caused by varied terminology, researchers advocate using \"eHHV-6A/B\" for inherited forms and reserving \"chromosomally integrated\" for somatic integrations only.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0105425"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Anellovirus constraint from 2 to 6 months postpartum followed by betatorquevirus and gammatorquevirus dominance in serum and milk. 产后2 ~ 6个月无虫病毒抑制,随后血清和乳汁中出现倍托尔克病毒和伽玛特克病毒优势。
IF 3.8 2区 医学
Journal of Virology Pub Date : 2025-07-31 DOI: 10.1128/jvi.00846-25
Anne L Timmerman, Antonia L M Schönert, Martin Deijs, Jacqueline van Rijswijk, Marit J van Gils, Johannes B van Goudoever, Britt J van Keulen, Lia van der Hoek
{"title":"Anellovirus constraint from 2 to 6 months postpartum followed by betatorquevirus and gammatorquevirus dominance in serum and milk.","authors":"Anne L Timmerman, Antonia L M Schönert, Martin Deijs, Jacqueline van Rijswijk, Marit J van Gils, Johannes B van Goudoever, Britt J van Keulen, Lia van der Hoek","doi":"10.1128/jvi.00846-25","DOIUrl":"https://doi.org/10.1128/jvi.00846-25","url":null,"abstract":"<p><p>Anelloviruses are ubiquitous, diverse viruses in the human virome not causing disease. In adults, the anellovirus composition (anellome) is dominated by alphatorqueviruses. However, infants seem to acquire their first anellovirus infections beginning with beta<i>-</i> and gammatorquevirus, soon followed by alphatorquevirus. Transmission via human milk is suggested as a potential transmission route. Consequently, we hypothesize that milk may contain predominantly beta- and gammatorqueviruses. That would also imply that compartmentalization between milk and serum takes place as the anellome in adults is dominated by alphatorqueviruses. We therefore examined anellovirus distribution in paired serum and milk samples of lactating mothers in the first 15 months after delivery (<i>n</i> = 30). Unexpectedly, genus-specific qPCRs revealed that the majority of serum and milk were negative for anelloviruses 2-6 months postpartum (4 serum and 1 milk positives out of 13), whereas positive from 6 months postpartum onwards (11 serum and 8 milk positives out of 16). Importantly, a dominance of beta- and gammatorquevirus in both serum and milk from 6 months postpartum was found. We also found significantly higher anellovirus loads in serum compared to milk, with no obvious difference in anellovirus genera presence between compartments. Anellovirus variant analysis using Oxford Nanopore sequencing revealed that 31 out of 45 variants were shared with the corresponding serum of the mother. We conclude that anellovirus compartmentalization between the circulation and the mammary glands could not be detected.</p><p><strong>Importance: </strong>Anelloviruses are omnipresent in the human population, yet their transmission routes, especially in early life, remain unclear. This study focused on compartmentalization between blood and the mammary gland to investigate the likelihood of virus transmission via milk. We show that serum and milk samples generally share anellovirus genera and lineages. Interestingly, serum as well as milk samples collected between 2 and 6 months postpartum tested mainly negative for anelloviruses, but those received thereafter were dominated by beta- and gammatorquevirus, reflecting the initial anellovirus colonizers observed in children.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0084625"},"PeriodicalIF":3.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Plasmid-like dynamics of persistent RNA viruses in the host fungal population. 宿主真菌群体中持久性RNA病毒的质粒样动力学。
IF 3.8 2区 医学
Journal of Virology Pub Date : 2025-07-31 DOI: 10.1128/jvi.00582-25
Yuto Chiba, Seiyo Watanabe, Ayano Ikeda, Shuhei Miyashita, Daisuke Hagiwara, Syun-Ichi Urayama
{"title":"Plasmid-like dynamics of persistent RNA viruses in the host fungal population.","authors":"Yuto Chiba, Seiyo Watanabe, Ayano Ikeda, Shuhei Miyashita, Daisuke Hagiwara, Syun-Ichi Urayama","doi":"10.1128/jvi.00582-25","DOIUrl":"https://doi.org/10.1128/jvi.00582-25","url":null,"abstract":"<p><p>Unlike the well-known acute or chronic animal and plant RNA viruses, most fungal RNA viruses (RNA mycoviruses) have a persistent life cycle. They lack an extracellular infection route and coexist with their hosts for a lifetime. RNA mycoviruses affect various biological properties of host fungi and are widespread across all major fungal groups. The frequency of fungal isolates harboring RNA mycoviruses ranges from a few percent to several tens of percent, indicating their high persistence within ecosystems. However, the dynamics of RNA mycoviruses and the maintenance mechanisms within host populations remain largely unknown. Here, we developed an experimental laboratory model system to examine the dynamics of mycoviruses within clonal host populations and to clarify the mechanisms. In our experimental system, we used two mycoviruses infecting <i>Aspergillus fumigatus</i>. Using this system, we discovered that viral prevalence changed according to environmental conditions (temperature or fungicide exposure). The driving forces behind these prevalence changes were viral horizontal transmission between isogenic strains through hyphal fusion, viral loss, and viral impact on host growth. Our findings indicated that the dynamics of mycoviruses are similar to those of plasmids in bacterial populations. This analogy implied an uncovered role of mycoviruses as a switching factor for fungal adaptation to changing environments.IMPORTANCEWhile RNA viruses are generally known for their ability to infect cells from the extracellular environment, a substantial diversity of RNA viruses, particularly those that persistently infect fungi, lack such infectivity. The ecological success and evolutionary maintenance of these persistent RNA viruses remain poorly understood. In this study, we experimentally demonstrate how a non-infectious RNA virus is transmitted and stably maintained within specific fungal host lineages. The revealed mechanism resembles the inheritance strategies of plasmids, highlighting a fundamentally different viral lifestyle that does not rely on extracellular horizontal transmission. These findings advance our understanding of virus-host interactions beyond the classical infection model and shed light on the evolutionary flexibility of RNA viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0058225"},"PeriodicalIF":3.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Validation of diverse and previously untraceable Sendai virus copyback viral genomes by direct RNA sequencing. 通过直接RNA测序验证多种以前无法追踪的仙台病毒反转录病毒基因组。
IF 3.8 2区 医学
Journal of Virology Pub Date : 2025-07-31 DOI: 10.1128/jvi.00894-25
Sarah E Pye, Emna Achouri, Yanling Yang, Abdulafiz Musa, Carolina B López
{"title":"Validation of diverse and previously untraceable Sendai virus copyback viral genomes by direct RNA sequencing.","authors":"Sarah E Pye, Emna Achouri, Yanling Yang, Abdulafiz Musa, Carolina B López","doi":"10.1128/jvi.00894-25","DOIUrl":"https://doi.org/10.1128/jvi.00894-25","url":null,"abstract":"<p><p>Copyback viral genomes (cbVGs) are truncated viral genomes with complementary ends produced when the negative-sense RNA virus polymerase detaches from the replication template and resumes elongation from the nascent strand. Despite advances in methods to identify cbVGs based on the site of polymerase break and rejoin, PCR-based tools cannot provide full-length sequences of most cbVGs and/or can introduce errors and artifacts during cbVG amplification. These limitations have painted an incomplete picture of the diverse population of cbVGs generated during infection. To improve our ability to obtain native full-length sequences of cbVGs, we optimized direct RNA sequencing (DRS) as a fast and simple tool to sequence full-length cbVGs and harnessed a BLAST-based analysis approach to identify cbVGs from long-read sequencing data. We analyzed the DRS outputs of multiple Sendai virus (SeV) stocks to highlight both the utility and limitations of this tool. We found that to capture the dominant 546 nt cbVG produced by SeV strain Cantell, the length of complementarity between the virus trailer and the DRS oligonucleotide should optimally be increased to up to 32 nt. We also demonstrate comparable quality of cbVG sequences by DRS from as little RNA as 17.6 ng from the media fraction or 50 ng from the cellular fraction of cells infected with SeV, in contrast to the recommended 1,000 ng. Importantly, we validated different cbVG species from two recombinant SeV stocks, including cbVGs whose break positions occurred at or near position one in the reference genome.IMPORTANCEMost viruses of the order Mononegavirales have been demonstrated to naturally generate copyback viral genomes. These genomes are critical determinants of infection outcomes; they interfere with standard virus replication by competing for viral resources, activate antiviral responses, and inhibit protein translation. Despite their critical roles in infection, current tools to study copyback viral genomes rely either on preexisting knowledge of the sequence of a target RNA or require reverse transcription and amplification of the target RNA, biasing toward short copyback genomes and introducing relatively high rates of errors. Here, we detail the optimization of direct RNA sequencing to validate native full-length copyback viral genomes, including species that have not been validated previously.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0089425"},"PeriodicalIF":3.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Membrane protein CRISPR screen identifies RPSA as an essential host factor for porcine epidemic diarrhea virus replication. 膜蛋白CRISPR筛选确定了猪流行性腹泻病毒复制的重要宿主因子RPSA。
IF 3.8 2区 医学
Journal of Virology Pub Date : 2025-07-30 DOI: 10.1128/jvi.00649-25
Yu Zhao, Guanghao Guo, Yumei Sun, Mengjia Zhang, Gan Yang, Zhongzhu Liu, Yanbin Song, Ahmed H Ghonaim, Ningning Ma, Mengdi Zhang, Anan Jongkaewwattana, Qigai He, Wentao Li
{"title":"Membrane protein CRISPR screen identifies RPSA as an essential host factor for porcine epidemic diarrhea virus replication.","authors":"Yu Zhao, Guanghao Guo, Yumei Sun, Mengjia Zhang, Gan Yang, Zhongzhu Liu, Yanbin Song, Ahmed H Ghonaim, Ningning Ma, Mengdi Zhang, Anan Jongkaewwattana, Qigai He, Wentao Li","doi":"10.1128/jvi.00649-25","DOIUrl":"https://doi.org/10.1128/jvi.00649-25","url":null,"abstract":"<p><p>Porcine epidemic diarrhea, caused by porcine epidemic diarrhea virus (PEDV), is one of the most devastating diseases in the global pig industry due to its high mortality rate in piglets. The host factors required for PEDV replication, including receptors, remain poorly understood. Here, we developed a porcine membrane-protein-scale CRISPR/Cas9 knockout (PigMpCKO) library and performed two rounds of PEDV infection. Ribosomal protein SA (RPSA), the known receptor of dengue virus, was found to be a potent host factor. Moreover, our research revealed that RPSA is involved in the replication stage of PEDV and not in the entry stage. Inhibitor and activator experiments demonstrated that knockout (KO) of RPSA downregulates the ERK1/2 signaling pathway to impair PEDV infection. Additionally, RNA sequencing data indicated that cellular lipid biosynthesis and lipid transport processes were significantly inhibited in the absence of RPSA during PEDV infection. Mechanistic studies revealed that the reduction in total cholesterol and triglyceride levels, resulting from RPSA KO, was partially mediated by the ERK1/2 pathway, leading to impaired lipid accumulation during PEDV replication. Interestingly, RPSA KO also significantly downregulated the expression of aminopeptidase N (APN) and inhibited infection by transmissible gastroenteritis virus (TGEV) and porcine deltacoronavirus (PDCoV), both of which belong to the swine enteric coronavirus group. In summary, our results establish RPSA as a novel host factor that is critical for coronavirus replication. This provides new insights into the mechanisms of virus-host interactions and paves the way for the development of broad-spectrum antiviral therapies.</p><p><strong>Importance: </strong>Swine enteric coronaviruses (SeCoVs) cause severe economic losses to the global swine industry and pose a potential threat to public health. Identification of receptors required for PEDV infection could develop novel targets for drug therapy and disease-resistant breeding. We conducted a CRISPR/Cas9 screen targeting membrane proteins in porcine kidney cells infected with PEDV to identify possible receptors and discovered numerous novel candidate host factors. Considering RPSA's known role as a receptor for multiple viruses, we focused on investigating its potential in coronavirus infection. Our results revealed that RPSA does not contribute to the entry stage but to the replication stage of coronavirus infection. We first reported the role that RPSA plays in the regulation of APN expression and lipid metabolism. RPSA is essential for PEDV and other SeCoVs replication, providing a novel insight into the search for the receptor of PEDV and identifying potential therapeutic targets for coronaviruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0064925"},"PeriodicalIF":3.8,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144742352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mutations differentially affecting the coronavirus Mac1 ADP-ribose binding and hydrolysis activities indicate that it promotes multiple stages of the viral replication cycle. 不同程度影响冠状病毒Mac1 adp核糖结合和水解活性的突变表明,它促进了病毒复制周期的多个阶段。
IF 3.8 2区 医学
Journal of Virology Pub Date : 2025-07-30 DOI: 10.1128/jvi.00623-25
Joseph J O'Connor, Anuradha Roy, Reem Khattabi, Catherine Kerr, Nancy Schwarting, Yousef M Alhammad, Philip Gao, Xiaoming Zhang, Xufang Deng, Anthony R Fehr
{"title":"Mutations differentially affecting the coronavirus Mac1 ADP-ribose binding and hydrolysis activities indicate that it promotes multiple stages of the viral replication cycle.","authors":"Joseph J O'Connor, Anuradha Roy, Reem Khattabi, Catherine Kerr, Nancy Schwarting, Yousef M Alhammad, Philip Gao, Xiaoming Zhang, Xufang Deng, Anthony R Fehr","doi":"10.1128/jvi.00623-25","DOIUrl":"https://doi.org/10.1128/jvi.00623-25","url":null,"abstract":"<p><p>All coronaviruses (CoVs) encode a conserved macrodomain, termed Mac1, in non-structural protein 3 (nsp3) that binds and hydrolyzes ADP-ribose covalently attached to proteins. Mac1 is a key virulence factor that counters antiviral ADP-ribosyltransferase (PARP) activity. Previously, we found that MHV strain JHM (JHMV) with a mutation in the adenine binding site, JHMV-D1329A, was extremely attenuated in all tested cell types as opposed to JHMV-N1347A, which only has a replication defect in bone marrow-derived macrophages (BMDMs). Interestingly, an N1347A/D1329A double mutant was unrecoverable, indicating an essential role for Mac1 in JHMV infection. We hypothesized that these mutations may impact different stages of the MHV life cycle. First, to clarify how these mutations affected the biochemical activities of Mac1, we generated Mac1 proteins encoding the same mutations. As expected, the D-A mutation was extremely defective in ADP-ribose binding but maintained enzyme activity. In contrast, we previously found that the N-A mutation had WT levels of ADP-ribose binding but low enzyme activity, confirming that these mutations differentially affect the biochemical functions of Mac1. Following infection, D1329A displayed a large defect in the accumulation of viral RNA compared to WT or N1347A in all cells tested. Alternatively, N1347A infection produced normal levels of viral RNA but produced reduced levels of viral protein in interferon-competent bone marrow-derived macrophages (BMDMs). These results suggest that Mac1 ADP-ribose binding and enzymatic activities promote different stages of the viral life cycle, demonstrating the critical importance of Mac1 for JHMV replication.</p><p><strong>Importance: </strong>Over the last three decades, coronaviruses have repeatedly demonstrated their potential to become significant veterinary and public health threats. Zoonotic transmission of the myriad known coronavirus strains will remain a concern, regardless of the advances in vaccines and treatment. One difficulty in anticipating the next coronavirus outbreak is its diverse lineage and high propensity for mutation and recombination. The coronavirus macrodomain, Mac1, is conserved among all known coronaviruses and is also conserved in the <i>Togaviridae</i> and <i>Hepeviridae</i> families. Mac1 is a key factor in viral replication and pathogenesis, but its role in the replication cycle remains unclear. A deeper investigation of Mac1 function will identify conserved antiviral mechanisms and aid in the development of Mac1 inhibitors that represent a novel strategy for antiviral therapeutics.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0062325"},"PeriodicalIF":3.8,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144742353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cytomegalovirus latency-the sum of subtleties. 巨细胞病毒潜伏期——细微之处的总和。
IF 3.8 2区 医学
Journal of Virology Pub Date : 2025-07-30 DOI: 10.1128/jvi.00664-25
Meaghan H Hancock, Patrizia Caposio, Donna Collins-McMillen, Nicole L Diggins, Byeong-Jae Lee, Samuel Medica, Daniel N Streblow, Timothy White, Andrew D Yurochko, Felicia Goodrum
{"title":"Cytomegalovirus latency-the sum of subtleties.","authors":"Meaghan H Hancock, Patrizia Caposio, Donna Collins-McMillen, Nicole L Diggins, Byeong-Jae Lee, Samuel Medica, Daniel N Streblow, Timothy White, Andrew D Yurochko, Felicia Goodrum","doi":"10.1128/jvi.00664-25","DOIUrl":"https://doi.org/10.1128/jvi.00664-25","url":null,"abstract":"<p><p>Human cytomegalovirus (HCMV) is a betaherpesvirus, which, like all herpesviruses, establishes a life-long latent infection while retaining the ability to reactivate its replicative program. While HCMV likely reactivates frequently and sporadically in healthy individuals and typically without disease, reactivation poses a serious disease threat in the immunocompromised. The latent program of HCMV is complex and has been challenging to define due to limitations in appropriate experimental model systems related to virus-host species specificity, limited identification of <i>in vivo</i> latent reservoirs, and the dynamic cellular differentiation of the hematopoietic latency reservoir that is directly linked to latency maintenance and reactivation phenotypes. Here, we review the current understanding of HCMV latency, with a focus on cross-cutting principles derived collectively from <i>in vitro</i> experimental culture models and <i>in vivo</i> animal models using the corresponding orthologs (CMVs) to HCMV.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0066425"},"PeriodicalIF":3.8,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144742351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The vaccinia virus protein, C16, promotes the ubiquitylation and relocalization of the antiviral E3 ubiquitin-ligase, TRIM25. 牛痘病毒蛋白C16促进抗病毒E3泛素连接酶TRIM25的泛素化和重新定位。
IF 3.8 2区 医学
Journal of Virology Pub Date : 2025-07-28 DOI: 10.1128/jvi.00898-25
Jianing Dong, Shu Yue Luo, Summer Smyth, Grace Melvie, Olivier Julien, Robert J Ingham
{"title":"The vaccinia virus protein, C16, promotes the ubiquitylation and relocalization of the antiviral E3 ubiquitin-ligase, TRIM25.","authors":"Jianing Dong, Shu Yue Luo, Summer Smyth, Grace Melvie, Olivier Julien, Robert J Ingham","doi":"10.1128/jvi.00898-25","DOIUrl":"https://doi.org/10.1128/jvi.00898-25","url":null,"abstract":"<p><p>Poxviruses co-opt the ubiquitin (Ub)-proteasome system (UPS) to facilitate virus replication, evade the innate immune response, and block programmed cell death of infected cells. Moreover, the UPS is an integral component of innate immune signaling pathways used by the host to respond to infection. To further elucidate how the UPS is engaged early during poxvirus infection, we quantified viral and cellular peptides with a Ub remnant motif (diGly peptides) from lysates of uninfected and vaccinia virus Copenhagen strain (VACV-Cop)-infected HeLa cells. Of note, we identified several ubiquitylated peptides from the cellular antiviral protein, TRIM25, that were enriched for, or exclusively found, in VACV-Cop-infected cells. TRIM25 is an E3 ligase for Ub and the Ub-like protein, ISG15, and TRIM25 performs several functions including activating the type I interferon response. Higher-molecular weight, ubiquitylated TRIM25 species were evident as early as 1 h post-infection of HeLa cells with VACV-Cop, and they persisted throughout infection. Proteasomal or lysosomal degradation did not appear to be a major consequence of this ubiquitylation; however, TRIM25 ubiquitylation correlated with its relocalization to punctate structures in infected cells. C16, a Bcl-2 family-like protein encoded by identical genes on both arms of the VACV-Cop genome, was both necessary and sufficient to promote TRIM25 ubiquitylation and relocalization. These phenomena were not evident in cells infected with Orthopoxviruses lacking the genes encoding for C16. We postulate that the ubiquitylation and/or relocalization of TRIM25 induced by C16 could represent a novel mechanism for poxviruses to subvert the host antiviral response.IMPORTANCEUbiquitylation is a versatile post-translational modification that is required for poxviruses to replicate their genomes and evade host cell defenses to infection. At the same time, both degradative and non-degradative protein ubiquitylation are critical components of the innate and adaptive immune responses to infection. In this study, we opted for a proteomics approach to examine changes in protein ubiquitylation early after vaccinia virus infection with the goal of identifying novel ways by which ubiquitylation is exploited during infection. We demonstrate that many Orthopoxviruses utilize the Bcl-2 family-like protein C16 to promote the ubiquitylation and relocalization of the cellular E3 ubiquitin/ISG15-ligase, TRIM25, which we hypothesize represents a novel strategy by which these viruses evade the host cell antiviral response. Moreover, our findings hint that Orthopoxviruses may also have C16-independent strategies to interfere with the function of TRIM25.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0089825"},"PeriodicalIF":3.8,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Transferrin receptor 1 (TfR1) functions as an entry receptor for scale drop disease virus to invade the host cell via clathrin-mediated endocytosis. 转铁蛋白受体1 (TfR1)是鳞状降病病毒通过网格蛋白介导的内吞作用侵入宿主细胞的入口受体。
IF 3.8 2区 医学
Journal of Virology Pub Date : 2025-07-28 DOI: 10.1128/jvi.00671-25
Jiaming Chen, Yuting Fu, Yong Li, Shaoping Weng, Hebing Wang, Jianguo He, Chuanfu Dong
{"title":"Transferrin receptor 1 (TfR1) functions as an entry receptor for scale drop disease virus to invade the host cell via clathrin-mediated endocytosis.","authors":"Jiaming Chen, Yuting Fu, Yong Li, Shaoping Weng, Hebing Wang, Jianguo He, Chuanfu Dong","doi":"10.1128/jvi.00671-25","DOIUrl":"https://doi.org/10.1128/jvi.00671-25","url":null,"abstract":"<p><p>Scale drop disease virus (SDDV), a distinct member of the genus <i>Megalocytivirus</i> within the <i>Iridoviridae</i> family, has emerged as a novel threat to global teleost aquaculture. Despite its importance, the pathogenic mechanism of SDDV remains largely elusive. In this study, we identified mandarin fish transferrin receptor 1 (<i>mf</i>TfR1) as an entry receptor for SDDV to invade host cells. First, <i>mf</i>TfR1 was detected in high abundance in purified SDDV virions and exhibited dynamic responses to SDDV infection, showing distinct regulatory patterns both <i>in vivo</i> and <i>in vitro</i>. Overexpression of <i>mf</i>TfR1 in low-permissive fathead minnow (FHM) cells significantly enhanced SDDV replication, particularly during the early stages of viral binding and entry. Conversely, antibody-blocking experiments and treatment with the TfR1 inhibitor ferristatin II significantly suppressed SDDV entry. Further investigation revealed that <i>mf</i>TfR1 directly interacted with the major capsid protein (MCP) of SDDV, and the helical domain of <i>mf</i>TfR1 was identified as the crucial docking site. The binding site within the helical domain was determined, and disrupting this interaction significantly reduced viral entry and host mortality. Finally, we demonstrated that SDDV could activate Src kinase-mediated tyrosine phosphorylation of <i>mf</i>TfR1. This phosphorylation event enhanced the internalization of <i>mf</i>TfR1 and facilitated clathrin-mediated endocytosis. Collectively, our study provides compelling evidence to confirm that <i>mf</i>TfR1 functions as an entry receptor that mediates SDDV entry into host cells via clathrin-mediated endocytosis, leading to a lethal infection outcome. Our work lays the groundwork for the development of targeted therapeutic strategies to mitigate the impact of SDDV in aquaculture.IMPORTANCETfR1, a dimeric glycoprotein classified as a type II transmembrane receptor, facilitates the cellular internalization of holo-transferrin. In several mammalian and avian RNA viruses and small DNA viruses, TfR1 serves as a crucial receptor to mediate the entry of viruses into host cells. As an emerging large DNA virus, SDDV poses an emerging threat to teleosts globally; however, its underlying pathogenic mechanisms remain poorly understood. In this study, we are the first to identify <i>mf</i>TfR1 as a crucial receptor for SDDV entry. We demonstrated a specific interaction between <i>mf</i>TfR1 and the major capsid protein (MCP) of SDDV, with the helical domain of <i>mf</i>TfR1 acting as the binding site. Moreover, we confirmed that SDDV enters cells through <i>mf</i>TfR1-mediated clathrin-dependent endocytosis. This work highlights the essential role of TfR1 in aquatic DNA viral infections and establishes the theoretical foundation for developing targeted therapeutic strategies against SDDV.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0067125"},"PeriodicalIF":3.8,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibition of interferon signaling improves rabbit calicivirus replication in biliary organoid cultures. 抑制干扰素信号传导可改善兔胆道类器官中杯状病毒的复制。
IF 4 2区 医学
Journal of Virology Pub Date : 2025-07-25 DOI: 10.1128/jvi.00574-25
Elena Smertina, Megan Pavy, Nias Y G Peng, Omid Fahri, Maria Jenckel, Tanja Strive, Michael Frese, Ina L Smith
{"title":"Inhibition of interferon signaling improves rabbit calicivirus replication in biliary organoid cultures.","authors":"Elena Smertina, Megan Pavy, Nias Y G Peng, Omid Fahri, Maria Jenckel, Tanja Strive, Michael Frese, Ina L Smith","doi":"10.1128/jvi.00574-25","DOIUrl":"https://doi.org/10.1128/jvi.00574-25","url":null,"abstract":"<p><p>The <i>Rabbit hemorrhagic disease virus</i> (RHDV) was discovered 40 years ago. This highly pathogenic virus threatens the integrity of ecosystems in the European rabbit's native range, while in Australia, it is used as a biocontrol tool to manage overabundant populations of feral European rabbits. Little is known about the life cycle of this virus due to the absence of a reliable cell culture system. In 2023, we developed a rabbit liver-derived organoid cell culture system that supports RHDV replication but is unable to sustain serial passaging in culture. Here, we report that the interferon signaling pathway inhibitor Ruxolitinib increases virus replication in organoid-derived monolayer cells and, for the first time, enables the serial passaging of RHDV in cell culture. Four consecutive passages were achieved with viral titers reaching the concentration of the initial virus stock as measured by real-time quantitative PCR. Immunofluorescence analysis showed that more cells are infected in the presence of Ruxolitinib. Furthermore, we noted that cells grew faster and formed healthier monolayers in the presence of the interferon inhibitor. To determine the cellular composition of the monolayers, we used single-cell RNA sequencing, revealing that our organoids consist largely of RHDV-permissive cholangiocytes.</p><p><strong>Importance: </strong>In this work, we describe the use of an interferon inhibitor to enhance the permissiveness of our recently developed rabbit liver-derived organoid cell culture system for rabbit hemorrhagic disease viruses. The data show that interferon inhibitors offer a simple and cost-effective approach to increase the replication of difficult-to-grow viruses in culture systems that are not interferon-deficient.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0057425"},"PeriodicalIF":4.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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