Journal of Virology最新文献

{"title":"Correction for Chen et al., \"N6-methyladenosine within transmissible gastroenteritis virus genomic RNA inhibits its replication via efficient recognition by RNA sensor RIG-I\".","authors":"Jianing Chen, Shengyu Lin, Qianzi Liu, Mengling Gao, Zemei Wang, Jiao Tang, Yaru Cui, Chen Tan, Guangliang Liu","doi":"10.1128/jvi.00380-26","DOIUrl":"https://doi.org/10.1128/jvi.00380-26","url":null,"abstract":"","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0038026"},"PeriodicalIF":3.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775408","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}

{"title":"Concanavalin A targets phylogenetically conserved N-linked glycans on coronavirus spike proteins for broad-spectrum antiviral activity.","authors":"Dekuan Guo, Shi Yu, Kaixiong Ma, Hua Tao, Qingxing Wang, Sirui Han, Qiangyun Ai, Huina Hu, Xiancai Ma, Geng Li, Shaobo Wang","doi":"10.1128/jvi.01679-25","DOIUrl":"https://doi.org/10.1128/jvi.01679-25","url":null,"abstract":"<p><p>The rapid evolution of SARS-CoV-2 variants, driven by antigenic drift in the spike glycoprotein, continues to undermine the efficacy of current vaccines and monoclonal antibody therapies. Targeting conserved features of the spike protein has been a major focus against coronavirus entry and the development of therapeutics. Here, we demonstrate that the plant lectin concanavalin A (ConA) broadly inhibits coronavirus entry through a conserved mechanism. With a combination of cell-cell fusion, pseudoviral entry, and authentic virus infection models, we show that ConA broadly inhibits coronavirus spike-mediated membrane fusion and viral entry. Biochemical analyses reveal that ConA targets two highly conserved N-glycosylation sites outside the receptor binding domain, flanking the S2' cleavage site via its mannose-binding properties. This interaction sterically impedes proteolytic activation of the spike, a molecular step essential for membrane fusion. ConA exhibited nanomolar efficacy against hCoV-NL63 infections <i>in vitro</i> and significantly reduced viral load and mitigated lung pathology in hCoV-NL63-infected mice <i>in vivo</i>. Our findings reveal specific N-linked glycosylation sites as a major vulnerability of the spike and highlight ConA as a prototype for the development of lectin-based therapeutics against emerging coronavirus infections.IMPORTANCEThe rapid evolution of SARS-CoV-2 variants, which evade current vaccines and therapeutics by altering epitopes on the spike protein, highlights a critical need for broad-spectrum antivirals. This study investigates concanavalin A (ConA), a legume lectin that targets highly conserved N-linked glycosylation sites on the spike protein, as a potential pan-coronavirus entry inhibitor. ConA broadly inhibits diverse coronaviruses by blocking spike-mediated membrane fusion. In contrast to previously reported antiviral lectins, ConA binds specifically to high-mannose oligosaccharides by targeting two phylogenetically conserved residues in the S2 subunit outside the receptor-binding domain. Consequently, ConA binding prevents the proteolytic activation of S2' and effectively inhibits membrane fusion and coronavirus infection both <i>in vitro</i> and <i>in vivo</i>. This work identifies conserved N-glycosylation sites on the spike protein as stable, vulnerable targets for antiviral intervention, distinct from the variable epitopes recognized by antibodies. These findings indicate that lectins like ConA may provide a promising approach for developing effective antivirals against emerging coronaviruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0167925"},"PeriodicalIF":3.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775392","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}

{"title":"Griffithsin-mediated inhibition of cellular entry of hemorrhagic fever viruses and insights into its mechanisms.","authors":"Takeshi Saito, Wakako Furuyama, Devinda S Muthusinghe, Yannick Munyeku-Bazitama, Takanari Hattori, Mami Okabe, Takeshi Yokoyama, Yoshikazu Tanaka, Ryuichi Sakai, Yasuteru Sakurai, Miako Sakaguchi, Rika Tsukagoshi, Noelia S Coronado Barrios, Thomas Tipih, Kyle Rosenke, Andrea Marzi, Manabu Igarashi, Shuzo Urata, Junki Maruyama, Asuka Nanbo, Ayato Takada","doi":"10.1128/jvi.00372-26","DOIUrl":"https://doi.org/10.1128/jvi.00372-26","url":null,"abstract":"<p><p>Griffithsin (GRFT), a lectin derived from the red algae <i>Griffithsia</i>, is known as an antiviral agent that binds to high-mannose glycans on viral envelope glycoproteins (GPs). In this study, we evaluated the antiviral activity of GRFT against Ebola virus (EBOV), Marburg virus (MARV), Lassa virus (LASV), Lujo virus (LUJV), and Crimean-Congo hemorrhagic fever virus (CCHFV), all of which cause severe and often fatal hemorrhagic fevers in humans. GRFT effectively blocked the entry of these viruses into cells, with stronger inhibition observed against LASV, LUJV, and CCHFV than against EBOV and MARV. This inhibitory effect depended on the lectin activity of GRFT, as its mutant lacking glycan-binding function completely lost the ability to inhibit the entry of these viruses into cells. We found that GRFT induced aggregation of virus-like particles (VLPs) derived from EBOV and MARV, whereas this activity was not observed with LASV- and LUJV-derived VLPs. Most of the escape mutants of LASV and LUJV GPs exhibited amino acid substitutions that likely disrupted GRFT binding by removing glycosylation sites at positions 79 and 73, respectively. Interestingly, other substitutions close to these positions, although unrelated to glycosylation, also contributed to reduced inhibitory activity of GRFT, suggesting a unique recognition mode in which both sugar chains and adjacent amino acid residues constitute the binding site structure for GRFT. Overall, our results provide insights into mechanisms underlying the antiviral effects of GRFT and highlight lectin-related activities as a key feature for broad-spectrum antiviral agents targeting highly glycosylated envelope GPs.</p><p><strong>Importance: </strong>Emerging and re-emerging infectious diseases, including viral hemorrhagic fevers, pose a major global health threat due to their potential for widespread outbreaks. Currently, treatment options for such diseases are limited and often ineffective against newly emerging viruses. Here, we demonstrate that Griffithsin (GRFT), a naturally derived lectin from red algae, inhibits the entry of multiple hemorrhagic fever viruses into host cells. By blocking key processes of the viral entry mediated by envelope glycoproteins, lectins such as GRFT can exhibit broad antiviral activity that could potentially overcome the limitations of existing treatments against emerging viruses. Our findings emphasize that targeting sugar chains and adjacent structures on viral glycoproteins with GRFT could provide a therapeutic strategy against diverse viral species. Such an approach is particularly valuable for newly emerging viruses for which specific countermeasures have not yet been established.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0037226"},"PeriodicalIF":3.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147774763","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}

{"title":"SARS-CoV-2 3CLpro mutations T21I and E166A confer differential resistance to simnotrelvir, bofutrelvir, and ensitrelvir.","authors":"Lu Chen, Haixia Su, Weijuan Shang, Tianqing Nie, Wenhua Kuang, Chenchen Wang, Qiang Shao, Leike Zhang, Wen Liu, Yechun Xu, Yumin Zhang","doi":"10.1128/jvi.02223-25","DOIUrl":"https://doi.org/10.1128/jvi.02223-25","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Inhibiting the catalytic activity of 3CLpro is a mainstream strategy to block coronavirus replication. However, the appearance of SARS-CoV-2 3CLpro resistance to protease inhibitors raises concerns for effective therapies. In this work, we first investigated the resistance profile of simnotrelvir, an approved anti-SARS-CoV-2 drug that targets 3CLpro. We found that the T21I/E166A mutations in 3CLpro equally emerged when SARS-CoV-2 was passaged in the HEK293T-hACE2 cells with increasing concentrations of simnotrelvir. The SARS-CoV-2 isolate carrying 3CLpro&lt;sup&gt;T21I/E166A&lt;/sup&gt; (SARS2-T21I/E166A) showed cross-resistance to simnotrelvir, nirmatrelvir, and ensitrelvir, but not significant resistance to bofutrelvir. Biochemical and cellular assays confirmed that 3CLpro&lt;sup&gt;T21I/E166A&lt;/sup&gt; was associated with the differential resistance to these protease inhibitors. Crystallographic structural analysis indicated that the alanine substitution disrupted hydrogen bonding interactions surrounding the γ-lactam rings (P1) of the inhibitors, which is similar to the model rebuilding observed with the previously reported E166V mutation. However, in contrast to the valine substitution, the alanine substitution resulted in a more spacious S2 subsite, thereby causing stronger interaction between the P1 and residues F140 and Ser1 of protomer B. Further computational simulations demonstrated that the covalent binding of bofutrelvir preserves strong binding affinity despite modifications in the S2 subsite caused by the E166A mutation, suggesting that inhibitors containing an aldehyde warhead may partially overcome resistance. Notably, both simnotrelvir and bofutrelvir exhibited therapeutic efficacy against the SARS2-T21I/E166A variant in K18-hACE2 mice. These findings advance our understanding of the resistance profiles and mechanistic underpinnings of SARS-CoV-2 3CLpro and underscore the necessity for diversified antiviral therapeutic strategies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Considering that the nirmatrelvir-resistant SARS-CoV-2 has emerged in immunocompromised patients who received long-term Paxlovid therapy, it is essential to investigate the response of resistance 3CLpro mutants to various protease inhibitors. Simnotrelvir, a novel inhibitor targeting SARS-CoV-2 3CLpro, has been authorized for the treatment of mild-to-moderate COVID-19 in China and has treated over 1 million patients. However, the resistance profile of simnotrelvir to SARS-CoV-2 remains unknown. Here, we identified that 3CLpro with T21I/E166A mutations confers resistance to simnotrelvir and showed cross-resistance to nirmatrelvir and ensitrelvir, but not bofutrelvir. More importantly, we further revealed that E166A showed a novel resistance mechanism to both the covalent inhibitors consisting of a γ-lactam ring and non-covalent inhibitors like ensitrelvir, which is different from that of E166V previously reported. In contrast, bofutrelvir maintains high affinity to T21I/E166A, suggest","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0222325"},"PeriodicalIF":3.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775145","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}

{"title":"Enterovirus D68 B3 clade strains are efficiently recovered from cDNA infectious clones in 293T cells and infect human spinal cord organoids.","authors":"Jennifer E Jones, Sarah Maya, Gal Yovel, Jessica Ciomperlik-Patton, Jennifer Anstadt, Megan Culler Freeman","doi":"10.1128/jvi.00450-26","DOIUrl":"10.1128/jvi.00450-26","url":null,"abstract":"<p><p>Enterovirus D68 (EV-D68) is associated with respiratory disease in children. Between 2014 and 2018, EV-D68 infection was linked to peaks of a polio-like neurologic condition called acute flaccid myelitis (AFM), but currently circulating strains are not. We hypothesized that specific mutations within B3 clade strains impact neurovirulence. Few studies have investigated B3 clade strains, and none have recovered these viruses from cDNA infectious clones to understand how novel mutations in B3 clade strains impact neurovirulence. In this study, we examine the neurovirulence of recovered (r) B3 clade strains in relevant human cell culture and 3D organoid models. We demonstrate that rB3 clade strains replicate efficiently in the permissive RD cell line and in human respiratory epithelial cell lines, with BEAS-2B cells exhibiting greater permissivity than A549 cells. rB3 clade strains infect neural cells, including SH-SY5Y cells, a neuroblastoma cell line, and human spinal cord organoids, which model the cellular heterogeneity of the spinal cord. Immunofluorescence staining confirmed infection, with viral antigen colocalized with neurons. These findings are consistent with previous studies from our laboratory and others on the neurovirulence of clinical isolates of B3 clade strains. Overall, we provide a critical platform for rigorous interrogation of viral determinants of neurovirulence within the B3 clade.IMPORTANCEEnterovirus D68 (EV-D68) can cause acute flaccid myelitis (AFM), a debilitating neurological condition of the spinal cord in children. Identifying viral determinants of EV-D68 neurovirulence is critical to understanding recent shifts in AFM prevalence; however, these investigations have been limited to a small subset of infectious clones distantly related to currently circulating B3 clade strains. In this study, we examine characteristics of recovered (r)EV-D68 strains from the dominant B3 clade. While all rEV-D68 replicate efficiently in a permissive cell line and in human respiratory epithelial cells, titers varied between strains in cultured neuroblastoma cells. Similarly, all B3 clade strains established infection in human spinal cord organoids, but replication varied between strains. Our study provides an essential platform for investigation into viral mutations within relevant B3 clade strains driving shifts in AFM prevalence.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0045026"},"PeriodicalIF":3.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775364","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}

{"title":"A single amino acid mutation in norovirus NS4 promotes viral spread.","authors":"Mridula Annaswamy Srinivas, Robert C Orchard","doi":"10.1128/jvi.00086-26","DOIUrl":"10.1128/jvi.00086-26","url":null,"abstract":"<p><p>Viruses can rapidly adapt and evolve to new, unfavorable environments due to their decreased replication fidelity, large reproductive index, and short life cycle. Often, these adaptations that enable increased fitness in a new, specialized environment come with a trade-off of decreased fitness in a standard, general environment. Understanding the mechanistic basis for these fitness trade-offs has provided important insight into vaccine development, mechanism of action of antivirals, and function of viral proteins. Here, we sought to identify how a specialist murine norovirus (MNV) could be converted to a jack of all trades through a novel mutation without genetic reversion. Previously, we found that a mutation in MNV (NS6^F182C) overcame restriction by host protein Trim7 but decreased the efficiency of viral polyprotein NS6-7 cleavage and resulted in attenuation of this virus. Here, we find that a single valine-to-isoleucine mutation in MNV non-structural protein NS4 (NS4^V11I) is sufficient to rescue the attenuated replication of NS6^F182C over multiple cycles of replication. However, NS4^V11I did not affect the defective polyprotein cleavage; instead, the mutation facilitates faster viral spread <i>in vitro</i> independent of interferon signaling. The emergence of this mutation in NS4^V11I suggests an unappreciated connection between NS4 and NS6 during norovirus replication and provides a system to define the unknown role of norovirus NS4 during infection.IMPORTANCEViruses and hosts are involved in a continuous arms race for survival. Often, when viruses evolve to specialize in specific host environments, they lose their versatility and become specialists, only able to grow in one setting. This feature has been leveraged to create live-attenuated vaccines, identify the mechanism of action of antivirals, and uncover fundamental aspects of viral replication. Using murine norovirus as a model system, we aim to understand how a virus can adapt to overcome replication inefficiencies imposed by a previously acquired adaptive mutation. Here, we identify an unexpected connection between two murine norovirus non-structural proteins and uncover a role for the viral protein NS4 in viral spread. Taken together, these data provide new insight into viral evolution and the functions of norovirus proteins.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0008626"},"PeriodicalIF":3.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775396","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}

{"title":"Identification of host lncRNAs that impact Venezuelan equine encephalitis virus TC-83 replication.","authors":"Mahgol Behnia, Chunyan Ye, Kim Somfleth, Olufunmilola M Oyebamiji, Kathryn J Brayer, Yan Guo, Scott A Ness, Ram Savan, Steven B Bradfute","doi":"10.1128/jvi.01353-25","DOIUrl":"https://doi.org/10.1128/jvi.01353-25","url":null,"abstract":"<p><p>Venezuelan equine encephalitis virus (VEEV) causes encephalitis in humans and equids, and there are no vaccines or therapeutics for humans. In recent years, non-coding RNAs have emerged as critical regulatory factors affecting different cellular pathways. Specifically, long non-coding RNAs (lncRNAs) have been identified as regulators of antiviral pathways; however, their role in VEEV infection has not been assessed. Here, we show differential expression of several lncRNAs in primary mouse target cells infected with a vaccine strain of VEEV (TC-83) but not a pathogenic strain (TrD). Among the differentially expressed genes (DEGs), suppressing lncRNA small nucleolar RNA host gene 15 (Snhg15) resulted in a 7-fold increase in TC-83 replication in primary mouse astrocytes. Knockdown of Snhg15 during TC-83 infection resulted in the suppression of ten genes, all of which were also increased during TC-83 infection along with Snhg15. Most of these genes are involved in antiviral responses. KEGG pathway analysis confirmed the suppression of both pattern recognition receptor and inflammatory pathways after Snhg15 knockdown. However, Snhg15 suppression did not significantly alter NF-kB signaling in TC-83-infected cells. These data are the first to identify lncRNA responses in encephalitic alphavirus infection and demonstrate important roles for these overlooked RNAs in VEEV infection.IMPORTANCEAlthough many studies have reported differential expression of lncRNAs during viral infections, the lncRNA response to VEEV infection and its functional roles have not been previously characterized. In this study, we provide the first comprehensive analysis of host lncRNA expression in primary cells that are targeted during VEEV infection. We demonstrate that the expression of specific host lncRNAs is altered during VEEV infection and that modulation of these lncRNAs changes the expression of host antiviral and inflammatory pathways and impacts viral replication. These findings advance our understanding of VEEV-host interaction and shed light on previously unappreciated regulatory layers of infection. Given the absence of approved vaccines or antiviral therapies for VEEV, our work identifies novel host factors that may serve as potential targets for the development of anti-VEEV therapeutics upon further investigation.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0135325"},"PeriodicalIF":3.8,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147774816","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}

{"title":"Ordered release of genomic RNA during icosahedral virus disassembly.","authors":"Yiyang Zhou, Andrew L Routh","doi":"10.1128/jvi.00053-26","DOIUrl":"https://doi.org/10.1128/jvi.00053-26","url":null,"abstract":"<p><p>Many icosahedral viruses release their genomes through a series of ordered conformational changes involving distinct disassembly intermediates. While previous studies have focused on rearrangements of the capsid protein shell, it remains unclear whether viral genomes undergo defined structural transitions or are released in a specific order. Here, we developed \"<i>PT-ClickSeq,</i>\" a next-generation sequencing platform that natively profiles viral nucleic acids exposed during particle disassembly without RNA extraction or fragmentation. Using Flock House virus (FHV) as a model, which forms two well-defined disassembly intermediates, we found that FHV releases its RNA genome in a conserved, ordered manner: the 5' and 3' termini and specific internal loci are exposed first. Distinct genomic regions exhibited different energy barriers to release, suggesting a programmed exposure process. Complementary \"vPAR-CL\" analysis revealed progressive loss of RNA-capsid interactions, with RNA-protein interactions anti-correlated with genome release. Together, these findings show that the encapsidated genome actively orchestrates viral disassembly rather than serving as a passive cargo.IMPORTANCEViruses need to strike a balance between structural rigidity and flexibility to achieve both sufficient protection and rapid release of packaged genome into host cells. During the process of genome delivery, many viruses undergo a programmed disassembly process through successive morphological changes, which give rise to partially disassembled virus particles, termed disassembly intermediates. It is important to study these intermediates as \"checkpoints\" to understand virus disassembly dynamics. We established a next-generation sequencing method that can monitor the RNA behavior during these conformational changes. We found that different regions of RNA were released with different energy thresholds, and the RNA release prioritized regions with low RNA-protein interactions. These findings shed light on the active role of the viral RNA in virus disassembly.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0005326"},"PeriodicalIF":3.8,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147774877","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}

{"title":"The host protein SSR4 mediates PRRSV-induced endoplasmic reticulum stress via interaction with Nsp2.","authors":"Yingchao Li, Hongyan Gao, Zhong Liu, Man Lu, Yang Shen, Yajing Xing, Yu Wang, Xiaotong Wu, Pingping Yang, Hongjie Yuan, Yanmeng Hou, Yumei Cai, Baoquan Li, Yihong Xiao","doi":"10.1128/jvi.00266-26","DOIUrl":"https://doi.org/10.1128/jvi.00266-26","url":null,"abstract":"<p><p>Porcine reproductive and respiratory syndrome (PRRS) is a major economic burden to the global swine industry. Here, we identify the endoplasmic reticulum (ER) translocon component SSR4 as a critical host factor co-opted by PRRSV. We demonstrate that the viral non-structural protein Nsp2 physically interacts with SSR4 via its PLP2 and hypervariable domains and selectively upregulates its expression during infection by prolonging its protein half-life. Functional studies revealed that SSR4 is a proviral factor essential for efficient PRRSV replication. Mechanistically, SSR4 is required for the full activation of the PRRSV-induced ER stress response, specifically modulating the PERK-eIF2α and IRE1α-XBP1 axes of the unfolded protein response. Notably, Nsp2 itself acts as a key inducer of ER stress and mediates the upregulation of SSR4, suggesting a potential feed-forward loop that sustains a virus-favorable ER environment. This relationship is finely balanced, as pharmacological disruption of ER homeostasis using either the inducer tunicamycin (TU) or the chemical chaperone 4-phenylbutyric acid (4-PBA) potently inhibited viral replication. Importantly, TU and another inducer, dithiothreitol, exhibited potent, broad-spectrum antiviral activity against multiple PRRSV genotypes in both cell lines and primary porcine alveolar macrophages. Our study delineates a novel pathogenesis model where PRRSV Nsp2 hijacks SSR4 to engineer a proviral ER stress niche. The Nsp2-SSR4-ER stress axis represents a promising target for the development of broad-spectrum antiviral strategies against PRRS.IMPORTANCEThis study provides significant insights into porcine reproductive and respiratory syndrome virus (PRRSV) pathogenesis by identifying a novel and specific virus-host interface. We demonstrate that PRRSV, through its Nsp2 protein, hijacks a specific component of the host endoplasmic reticulum (ER) translocon SSR4 to orchestrate a tailored ER stress response conducive to viral replication. This mechanism is distinct from a general disruption of the TRAP complex, highlighting a precise viral strategy. Furthermore, the finding that pharmacological agents, which dysregulate this hijacked pathway-particularly ER stress inducers-act as potent, broad-spectrum antivirals challenges the conventional view of ER stress as a uniformly host-protective response. Our work not only uncovers a key molecular determinant of PRRSV replication but also validates the Nsp2-SSR4-ER stress axis as a promising and novel target for the development of much-needed, broad-spectrum therapeutic interventions against this economically devastating swine pathogen.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0026626"},"PeriodicalIF":3.8,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775176","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}

{"title":"Behind the membranous curtain-lipid dynamics and functions in coronaviral replication.","authors":"Florian Salisch, Christin Müller-Ruttloff","doi":"10.1128/jvi.01753-25","DOIUrl":"https://doi.org/10.1128/jvi.01753-25","url":null,"abstract":"<p><p>Lipids are naturally occurring hydrophobic biomolecules characterized by remarkable structural diversity. This includes various types of head groups, varying fatty acid chain lengths, degrees of unsaturation, and stereochemical configurations. Such variability enables lipids to serve multiple biological functions, such as forming membranes, storing energy, and facilitating signaling. Given their diverse roles, it is not surprising that approximately 5% of genes in eukaryotic cells are involved in lipid biosynthesis pathways. The multifunctional nature of lipids also makes them attractive targets for pathogens, including viruses, as cellular lipids are involved in and manipulated throughout every stage of viral replication. In the initial phase of replication, viruses exploit existing cellular lipids for entry and trafficking. After the replication is established and viral proteins are processed, extensive reprogramming of lipid synthesis and redistribution supports viral replication, assembly, and other processes. This review focuses on how coronaviruses, especially severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), utilize different lipid species and related cellular enzymes to interfere with lipid dynamics and functions and how this affects the different stages of coronaviral replication <i>in vitro</i>. Besides illuminating virus-host lipid interactions, this review identifies remaining open questions and promising new avenues for future mechanistic research.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0175325"},"PeriodicalIF":3.8,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729298","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}