Journal of VirologyPub Date : 2025-03-18Epub Date: 2025-02-11DOI: 10.1128/jvi.02172-24
Saptarshi Ghosh, Banani Mondal, Ola Jassar, Murad Ghanim, Saurabh Gautam, Vamsidhar Reddy Netla, Rajagopalbabu Srinivasan
{"title":"Begomovirus capsid proteins interact with cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase of its whitefly vector and modulate virus retention within its vector.","authors":"Saptarshi Ghosh, Banani Mondal, Ola Jassar, Murad Ghanim, Saurabh Gautam, Vamsidhar Reddy Netla, Rajagopalbabu Srinivasan","doi":"10.1128/jvi.02172-24","DOIUrl":"10.1128/jvi.02172-24","url":null,"abstract":"<p><p>Begomoviruses are whitefly-transmitted ss-DNA viruses that infect dicotyledonous plants and contribute to major economic losses to global crop production. Invasion and establishment of an aggressive cryptic species of <i>Bemisia tabaci</i>, known as the B cryptic species, has severely constrained vegetable production in the southeastern and southwestern United States. Disruption of genes/pathways critical for whitefly-mediated transmission can be effective for the management of begomoviruses. In this study, yeast two-hybrid (Y2H)-based screening of <i>B. tabaci</i> cDNA library identified a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase-4 (PDE4) of the whitefly as an interacting partner with capsid proteins (CPs) of old- and new-world begomoviruses. Interactions of PDE4 with begomovirus CPs were validated by glutathione-S-transferase (GST) pull-down assay and co-immunolocalization in whitefly midgut. The PDE4 family of enzymes hydrolyzes cAMP and regulates intracellular cAMP levels. This study conclusively proves that acquisition of begomoviruses downregulates the expression of PDE4 (mRNA and protein) resulting in elevated cAMP levels within the whitefly. The role of cAMP post virus acquisition is further elucidated wherein elevation of cAMP by chemical inhibition or gene (PDE4) silencing resulted in increased retention and transmission of begomoviruses. Similarly, decreased cAMP levels resulted in reduced begomovirus retention. The results of this study demonstrate that whitefly-mediated transmission of begomoviruses is regulated by intracellular cAMP by unknown mechanisms.</p><p><strong>Importance: </strong>Begomoviruses, transmitted by the sweetpotato whitefly (<i>Bemisia tabaci</i> Gennadius), are the causal agents of many economically important plant virus diseases. Lack of host plant resistance against begomoviruses, high whitefly abundance, and whitefly's ability to develop insecticide resistance rapidly often render the commonly used management practice ineffective. This study demonstrates how begomovirus retention within whitefly and its transmission can be modulated by altering cyclic adenosine monophosphate (cAMP) expression of its insect vector. Naturally occurring bio-pesticides that target insect cAMPs are known. Our findings can lead to alternative strategies for the management of begomoviruses by targeting whitefly cAMP using chemicals, botanicals, or RNAi-based insecticides.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0217224"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of VirologyPub Date : 2025-03-18Epub Date: 2025-02-13DOI: 10.1128/jvi.00018-25
Huixin Zhu, Jinxiu Lou, Zhen Yang, Juan Bai, Ping Jiang, Xianwei Wang, Xing Liu
{"title":"STT3B promotes porcine epidemic diarrhea virus replication by regulating N-glycosylation of PEDV S protein.","authors":"Huixin Zhu, Jinxiu Lou, Zhen Yang, Juan Bai, Ping Jiang, Xianwei Wang, Xing Liu","doi":"10.1128/jvi.00018-25","DOIUrl":"10.1128/jvi.00018-25","url":null,"abstract":"<p><p>Porcine epidemic diarrhea virus (PEDV), a highly pathogenic enteric coronavirus, has caused significant economic losses worldwide in recent years. The PEDV spike (S) protein has been reported to undergo extensive N-glycosylation, suggesting that glycosylation plays a crucial role in PEDV replication. In this study, we demonstrated that the N-glycosylation pathway promotes PEDV replication by facilitating the glycosylation of the S protein. First, we observed that pharmacological inhibition of host N-glycosylation using specific inhibitors significantly reduces viral replication. Furthermore, genetic ablation of STT3A or STT3B, the catalytically active subunits of the oligosaccharyltransferase (OST) complex, revealed that the STT3B-OST complex, but not STT3A, is preferentially required for PEDV replication. Notably, we showed that the N-glycosylation of the PEDV S protein depends on the oligosaccharyltransferase activity of STT3B. Together, the study demonstrated the critical role of the N-glycosylation pathway in PEDV replication by elucidating the relationship between the N-glycosylation of the PEDV S protein and STT3B, thereby presenting a potential new target for the prevention and control of PEDV.IMPORTANCEThe highly N-glycosylated spike protein of porcine epidemic diarrhea virus (PEDV) is a multifunctional protein that plays a crucial role in the viral replication cycle. In this study, using pharmacological inhibitors, we demonstrated the importance of the N-glycosylation pathway in PEDV replication. Genetic analysis revealed that STT3B, one of the catalytically active subunits of the oligosaccharyltransferase complex, promotes viral proliferation by regulating the N-glycosylation of the PEDV spike protein. Our findings enhance the understanding of the role of the N-glycosylation pathway in viral infection and identify STT3B as a potential therapeutic target for controlling PEDV infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0001825"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of VirologyPub Date : 2025-03-18Epub Date: 2025-02-26DOI: 10.1128/jvi.02165-24
Wentao Li, Basav N Hangalapura, Paul van den Elzen, Erwin van den Born, Frank J M van Kuppeveld, Peter J M Rottier, Berend-Jan Bosch
{"title":"Spike gene variability in porcine epidemic diarrhea virus as a determinant for virulence.","authors":"Wentao Li, Basav N Hangalapura, Paul van den Elzen, Erwin van den Born, Frank J M van Kuppeveld, Peter J M Rottier, Berend-Jan Bosch","doi":"10.1128/jvi.02165-24","DOIUrl":"10.1128/jvi.02165-24","url":null,"abstract":"<p><p>Porcine epidemic diarrhea virus (PEDV) is a pathogenic coronavirus that targets the swine intestinal tract, leading to acute diarrhea and high mortality in neonatal piglets. PEDV is categorized into different genotypes based on genetic variations, especially in the spike (S) gene. The S protein is crucial for viral entry and a major immune target. Significant differences in virulence have been observed among PEDV genotypes, particularly between classical strains and newly emerging strains. In this study, we explored the impact of spike gene variability on PEDV pathogenicity. Using targeted RNA recombination, we generated recombinant PEDV (rPEDV) variants carrying spike genes from contemporary strains (moderately virulent strain UU and highly virulent strain GDU), all within the genetic background of the avirulent DR13 vaccine strain. Pathogenicity was assessed in 3-day-old piglets. The rPEDV carrying the DR13 spike gene was nonpathogenic, with no detectable viral RNA in feces. The rPEDV with the UU spike gene induced mild to severe diarrhea, with moderate viral shedding but no mortality. Conversely, the rPEDV with the GDU spike gene caused severe diarrhea, high viral titers, and high mortality. These findings highlight the critical role of the spike protein in PEDV virulence, informing future development of effective control strategies, including the design of live-attenuated vaccines.IMPORTANCEThis study significantly advances our understanding of how genetic variations in the spike (S) protein of porcine epidemic diarrhea virus (PEDV) influence its ability to cause disease. By engineering viruses with spike genes from different PEDV strains, variations in this protein could be directly linked to differences in disease severity. We found that the spike protein from highly virulent strains caused severe diarrhea and high mortality in piglets, while that from less virulent strains led to milder symptoms. These findings emphasize the central role of the spike protein in determining PEDV virulence, which may enable the design of more effective vaccines to combat PEDV and reduce its impact on the swine industry.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0216524"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of VirologyPub Date : 2025-03-18Epub Date: 2025-02-05DOI: 10.1128/jvi.01700-24
Yi-Heng Huang, Xin-Lu Guo, Meng-Ke Shan, Gui-Wen Yang, Hui-Ting Yang
{"title":"Class B scavenger receptor resists WSSV replication by recognizing the viral lipid molecule and promoting phagocytosis.","authors":"Yi-Heng Huang, Xin-Lu Guo, Meng-Ke Shan, Gui-Wen Yang, Hui-Ting Yang","doi":"10.1128/jvi.01700-24","DOIUrl":"10.1128/jvi.01700-24","url":null,"abstract":"<p><p>Class B scavenger receptors (SRBs) have been well-studied in bacteria-induced immune responses in invertebrates. However, the status of SRB-defending viruses remains unclear. In this study, we identified a scavenger receptor in <i>Procambarus clarkii</i> (crayfish), which is homologous to mammalian SRBs, and designated it as <i>Pc</i>SRB. The expression of <i>Pc</i>SRB was upregulated after the WSSV challenge. The survival rate of crayfish was decreased, but the WSSV copy number increased after <i>Pc</i>SRB knockdown during virus invasion. In addition, <i>Pc</i>SRB bound to WSSV. Furthermore, we detected how <i>Pc</i>SRB interacted with WSSV, and we found that <i>Pc</i>SRB could bind to cholesta-3,5-diene, (CD3,5), a novel WSSV lipid ligand, rather than dibutyl phthalate (DBP). Besides, <i>Pc</i>SRB could bind to VP19, VP26, and VP28, rather than VP24. Mutant-binding experiments demonstrated that the hydrophobic domain (130-180 aa) of <i>Pc</i>SRB is important for recognizing WSSV. Furthermore, <i>Pc</i>SRB might promote lysosomal eliminating function to degrade WSSV. Altogether, we identified a new mechanism for scavenger receptor recognition and resistance to WSSV.IMPORTANCE<i>Pc</i>SRB could bind to WSSV directly. <i>Pc</i>SRB could interact with WSSV via binding to lipid molecule CD3,5 and viral envelope proteins. <i>Pc</i>SRB could influence lysosomal activation.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0170024"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Amino acid substitutions in NSP6 and NSP13 of SARS-CoV-2 contribute to superior virus growth at low temperatures.","authors":"Yuri Furusawa, Maki Kiso, Ryuta Uraki, Yuko Sakai-Tagawa, Hiroyuki Nagai, Michiko Koga, Yukie Kashima, Masayuki Hojo, Noriko Iwamoto, Kiyoko Iwatsuki-Horimoto, Norio Ohmagari, Yutaka Suzuki, Hiroshi Yotsuyanagi, Peter J Halfmann, Wataru Kamitani, Seiya Yamayoshi, Yoshihiro Kawaoka","doi":"10.1128/jvi.02217-24","DOIUrl":"10.1128/jvi.02217-24","url":null,"abstract":"<p><p>In general, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates well at 37°C, which is the temperature of the human lower respiratory tract, but it poorly at 30°C‒32°C, which is the temperature of the human upper respiratory tract. The replication efficiency of SARS-CoV-2 in the upper respiratory tract may directly affect its transmissibility. In this study, an XBB.1.5 isolate showed superior replicative ability at 32°C and 30°C, whereas most other Omicron sub-variant isolates showed limited growth. Deep sequencing analysis demonstrated that the frequencies of viruses possessing the NSP6-S163P and NSP13-P238S substitutions increased to more than 97% during propagation of the XBB.1.5 isolate at 32°C but did not reach 55% at 37°C. Reverse genetics revealed that these substitutions contributed to superior virus growth <i>in vitro</i> at these low temperatures by improving virus genome replication. Mutant virus possessing both substitutions showed slightly higher virus titers in the upper respiratory tract of hamsters compared to the parental virus; however, transmissibility between hamsters was similar for the mutant and parental viruses. Taken together, our findings indicate that NSP6-S163P and NSP13-P238S contribute to superior virus growth at low temperatures <i>in vitro</i> and in the upper respiratory tract of hamsters.</p><p><strong>Importance: </strong>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates efficiently at 37°C. However, the temperature of the human upper airway is 30°C-32°C. Therefore, the replicative ability of SARS-CoV-2 at low temperatures could influence virus replication in the upper airway and transmissibility. In this study, we assessed the growth of Omicron sub-variants at low temperatures and found that an XBB.1.5 isolate showed increased replicative ability. By deep sequencing analysis and reverse genetics, we found that amino acid changes in NSP6 and NSP13 contribute to the low-temperature growth; these changes improved RNA polymerase activity at low temperatures and enhanced virus replication in the upper airway of hamsters. Although these substitutions alone did not drastically affect virus transmissibility, in combination with other substitutions, they could affect virus replication in humans. Furthermore, since these substitutions enhance virus replication in cultured cells, they could be used to improve the production of inactivated or live attenuated vaccine virus.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0221724"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of VirologyPub Date : 2025-03-18Epub Date: 2025-02-04DOI: 10.1128/jvi.01676-24
Rachel D Pascoe, Youry Kim, Ajantha Rhodes, Jesslyn Ong, Carolin Tumpach, Celine Gubser, J Judy Chang, James H McMahon, Sharon R Lewin, Thomas A Rasmussen
{"title":"Targeting Ikaros and Aiolos with pomalidomide fails to reactivate or induce apoptosis of the latent HIV reservoir.","authors":"Rachel D Pascoe, Youry Kim, Ajantha Rhodes, Jesslyn Ong, Carolin Tumpach, Celine Gubser, J Judy Chang, James H McMahon, Sharon R Lewin, Thomas A Rasmussen","doi":"10.1128/jvi.01676-24","DOIUrl":"10.1128/jvi.01676-24","url":null,"abstract":"<p><p>HIV persists in people living with HIV (PLHIV) on antiretroviral therapy (ART) in long-lived and proliferating latently infected CD4+ T cells that selectively express pro-survival proteins, including the zinc finger proteins, Ikaros and Aiolos. In this study, we investigated whether pomalidomide, an immunomodulatory agent that induces degradation of Ikaros and Aiolos, could increase the death of HIV-infected cells and/or reverse HIV latency. Using an <i>in vitro</i> model of CD4+ T cells infected with a green fluorescent protein (GFP) reporter virus, pomalidomide increased the expression of the pro-survival protein B cell lymphoma (Bcl)-2 and did not increase apoptosis of GFP+ HIV productively infected CD4+ T cells. Pomalidomide also increased the expression of CD155 and UL16-binding protein (ULBP) stress proteins on GFP+ HIV productively infected CD4+ T cells, but this did not translate to enhanced clearance following co-culture with a natural killer (NK) cell line. Using CD4+ T cells from PLHIV on ART, pomalidomide <i>ex vivo</i> activated memory CD4+ T cells resulting in elevated HLA-DR expression and induced CD4+ T cell proliferation but only in the presence of T cell receptor stimulation with anti-CD3 and anti-CD28. There was no effect on cell-associated HIV RNA or the frequency of intact HIV DNA. In conclusion, despite an increase in stress protein expression, promoting Ikaros and Aiolos degradation in CD4+ T cells using pomalidomide did not directly induce apoptosis of HIV-infected cells or induce HIV latency reversal.<b>IMPORTANCE</b>People living with HIV (PLHIV) require lifelong antiretroviral therapy (ART) due to the persistence of latently infected cells. The zinc finger proteins, Ikaros and Aiolos, have recently been implicated in promoting the persistence of latently infected cells. In this study, we investigated the effects of pomalidomide, an immunomodulatory imide drug that induces the degradation of Ikaros and Aiolos, on HIV latency reversal and death of infected cells. Using CD4+ T cells from people living with HIV on suppressive antiretroviral therapy, as well as an <i>in vitro</i> model of productive HIV infection, we found that pomalidomide induced T cell activation and expression of stress proteins but no evidence of latency reversal or selective death of infected cells.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0167624"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"FBXO45 restricts HIV-1 replication by inducing SQSTM1/p62-mediated autophagic degradation of Tat.","authors":"Mingxiu Xu, Haobo Hu, Weijing Yang, Jiaxiang Zhang, Hong Wang, Wenyan Zhang, Chen Huan","doi":"10.1128/jvi.01912-24","DOIUrl":"10.1128/jvi.01912-24","url":null,"abstract":"<p><p>As a key regulator of human immunodeficiency virus type 1 (HIV-1) transcription, Tat plays an essential role in viral replication and latency, making it a promising target for designing viral control strategies. Identifying host factors that modulate Tat and exploring the underlying mechanisms will benefit our understanding of HIV-1 transcriptional regulation and provide valuable insights into Tat-based therapeutic strategies. Here, by employing the TurboID approach, we discovered high-affinity binding between FBXO45 and Tat. Our findings demonstrate that FBXO45 negatively regulates Tat by promoting Tat ubiquitination and directing it to autophagic degradation. Autophagic degradation of Tat has been reported, but the specific underlying mechanisms remain unidentified. We elucidated this issue by providing evidence that FBXO45-mediated Tat polyubiquitination is an essential prerequisite for this process. Silencing of FBXO45 leads to a deficiency of autophagy receptor SQSTM1/p62 to bind and facilitate the autophagic degradation of Tat. Our results further underscore the crosstalk between post-translational modifications of Tat by demonstrating that the phosphorylation site of the Tat S62 residue is required for ubiquitination induced by FBXO45. Furthermore, in the context of the regulation of HIV-1, FBXO45 inhibits viral replication and maintains the latency of HIV-1 by suppressing viral transcription. Importantly, FBXO45 overexpression significantly attenuated viral rebound after antiretroviral therapy withdrawal. In summary, our findings suggest a novel role for FBXO45 in regulating HIV-1 replication by inducing the ubiquitination and SQSTM1/p62-dependent autophagic degradation of Tat. Considering the indispensable role of Tat in the regulation of HIV-1 replication and reactivation, FBXO45 may be a potential target for therapeutic intervention against HIV-1.IMPORTANCEHIV-1 Tat plays an indispensable role in regulating viral transcription and is a promising target for achieving a functional cure for AIDS. Identifying the host factors that modulate Tat expression could benefit the development of anti-HIV-1 strategies targeting Tat. Using TurboID assay, we identified a significant interaction between FBXO45 and Tat. Functionally, FBXO45 ubiquitinates and directs Tat for SQSTM1/p62-mediated autophagic degradation, thereby effectively restricting HIV-1 replication and maintaining HIV-1 latency by suppressing Tat-dependent viral transcription. These findings uncover a novel role for FBXO45 in regulating Tat and broaden our understanding of the host mechanisms involved in Tat processing.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0191224"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11916737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of VirologyPub Date : 2025-03-18Epub Date: 2025-02-07DOI: 10.1128/jvi.01422-24
Benedikt Litz, Leonie F Forth, Florian Pfaff, Martin Beer, Michael Eschbaumer
{"title":"Distinct mutations emerge in the genome of serotype O foot-and-mouth disease virus during persistence in cattle.","authors":"Benedikt Litz, Leonie F Forth, Florian Pfaff, Martin Beer, Michael Eschbaumer","doi":"10.1128/jvi.01422-24","DOIUrl":"10.1128/jvi.01422-24","url":null,"abstract":"<p><p>Like other RNA viruses, foot-and-mouth disease virus (FMDV) has a high mutation rate. After the acute phase of infection, about half of infected cattle develop a persistent FMDV infection that can last for weeks or months. During this persistent phase, the virus continues to replicate, resulting in the emergence of genomic heterogeneity. We have documented the pattern of mutations in the persistent phase by obtaining consensus-level sequences directly from oropharyngeal fluid (OPF) without prior virus isolation in culture. OPF samples were repeatedly collected from 22 experimentally infected cattle, 20 of which were virus positive in the OPF on day 21 after infection or later. We observed that during the persistent phase, the amount of non-synonymous mutations causing an amino acid change increased over time. Two amino acid changes that showed a striking increase during the persistent phase, VP3 A75T and VP2 Y79H, were present neither in the inoculum nor during the acute phase. Another amino acid change in VP3, R56C, which was previously implicated in FMDV pathogenicity, was already present in the inoculum and dominated toward the end of the trial in most samples. Several other amino acid changes occurred, particularly on the surface of VP2 around residue VP2 79. By functional analysis, we show that the persistent isolates evolve distinctly compared with cell culture adaptation but do not show signs of antigenic escape from neutralizing antibodies. In agreement with previous observations, we conclude that these amino acid changes are indeed associated with persistent infection of cattle with FMDV serotype O.</p><p><strong>Importance: </strong>Our research article describes the genetic changes that occur during the acute and persistent foot-and-mouth disease (FMDV) infection. This is of particular interest to understand viral dynamics within an infected population from which new viral strains could emerge. Especially FMDV, with its high antigenic diversity and very limited cross-reactivity between strains and serotypes, has already demonstrated in the past that new variants can quickly emerge and evade vaccine responses. In our study, we have observed that this dynamic evolution continues during the persistent phase. Persistently infected animals, which are clinically indistinguishable from healthy animals, also pose a reservoir for recombination. A better understanding of viral dynamics is essential for improved vaccines to prevent the emergence of antigenic variants.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0142224"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qiu Zhong, Jiaxin Qi, Na Su, Zi Li, Chengcheng Wang, Hui Zeng, Ruiling Liu, Yuchen Li, Qian Yang
{"title":"<i>In vivo</i> investigation of PEDV transmission via nasal infection: mechanisms of CD4<sup>+</sup> T-cell-mediated intestinal infection.","authors":"Qiu Zhong, Jiaxin Qi, Na Su, Zi Li, Chengcheng Wang, Hui Zeng, Ruiling Liu, Yuchen Li, Qian Yang","doi":"10.1128/jvi.01761-24","DOIUrl":"https://doi.org/10.1128/jvi.01761-24","url":null,"abstract":"<p><p>The porcine epidemic diarrhea virus (PEDV), a highly pathogenic coronavirus, poses significant challenges to global swine agriculture with severe economic consequences. Our research reveals that in addition to known transmission routes, PEDV can be airborne, initially invading the nasal mucosa and subsequently being transported by dendritic cells and peripheral blood T cells, ultimately leading to intestinal disease in piglets. This study elucidates the cellular mechanisms behind the process, demonstrating how PEDV is internalized by CD4<sup>+</sup> T cells after being transferred by dendritic cells, where it establishes a latent infection. Crucially, PEDV induces the upregulation of the integrin α4β7 homing receptor, facilitating the migration of these infected CD4<sup>+</sup> T cells to the small intestine. Furthermore, our findings reveal that the activation of the α4β7-Rho-GTPases-Cofilin signaling pathway by PEDV reorganizes the actin cytoskeleton, enabling CD4<sup>+</sup> T-cell transmigration through high endothelial venules into the intestinal mucosa, resulting in the infection of intestinal epithelial cells. These insights not only illuminate the molecular mechanisms PEDV employs to hijack CD4<sup>+</sup> T cells for transmission from the respiratory tract to the intestine but also identify novel targets for therapeutic intervention, providing new perspectives for effectively preventing and managing PEDV infection with broader implications for controlling similar pathogens in diverse hosts.IMPORTANCEPorcine epidemic diarrhea virus (PEDV), characterized by rapid transmission and widespread prevalence, poses a significant long-term threat to the global pig farming industry. Our previous research revealed that, in addition to the classic fecal-oral infection route, PEDV can invade through the nasal mucosa, leading to intestinal infection. This study further investigated the molecular mechanisms by which the virus is transported by T lymphocytes from the respiratory tract to the intestines. We found that PEDV establishes a latent infection in CD4<sup>+</sup> T cells and promotes their intestinal homing by upregulating the homing receptor integrin α4β7. Additionally, we elucidated the activation of the integrin α4β7-mediated Rho-GTPase-Cofilin signaling axis by PEDV, which regulates pseudopod formation and facilitates CD4<sup>+</sup> T-cell migration to the intestinal mucosal lamina propria post-homing. This study elucidates the mechanism underlying the lymphocyte-dependent dissemination of PEDV following nasal infection, providing new insights into strategies for preventing PEDV invasion.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0176124"},"PeriodicalIF":4.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649603","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}
Oscar Lam, Esther Shaffer, Guney Boso, Christine A Kozak
{"title":"Intact, recombinant, and spliced forms of endogenous mouse mammary tumor viruses in inbred and wild mice.","authors":"Oscar Lam, Esther Shaffer, Guney Boso, Christine A Kozak","doi":"10.1128/jvi.00079-25","DOIUrl":"https://doi.org/10.1128/jvi.00079-25","url":null,"abstract":"<p><p>Endogenous retroviruses (ERVs) are chromosomally integrated viral copies that represent relics of past infections. Analysis of the sequenced genomes of 17 mouse strains, <i>Mus musculus</i> subspecies, and <i>Mus spretus</i> identified 29 ERVs of mouse mammary tumor viruses (MMTVs), termed <i>Mtvs</i>. The 15 laboratory mouse <i>Mtvs</i> are each present in multiple strains reflecting their common breeding history; most predate the development of inbred strains and were likely acquired by <i>Mus musculus domesticus</i> progenitors but have no orthologs in wild mice, whereas four, including the intact <i>Mtv1</i>, were likely endogenized more recently. One of the 14 <i>Mtvs</i> found in wild mice was distributed over a broad geographic range in southeast Asia. Most <i>Mtvs</i> are full-length, with multiple open reading frames, but <i>Mtvs</i> from many wild mice have an unusual envelope deletion corresponding to an intron of the viral <i>rem</i> accessory gene, suggesting its derivation from spliced MMTV cDNAs. These deleted <i>envs</i> have open reading frames, are found in globally distributed mice, and show subspecies-specific sequence variation consistent with their recurrent generation. The highly variable MMTV <i>sag</i> gene, responsible for resistance to exogenous infection, exhibits evidence of recombination as well as positive selection, consistent with its role in antiviral defense. In contrast, the spread of <i>Mtvs</i> in <i>Mus musculus</i> populations is not marked by an active arms race pitting the MMTV envelope against its cellular receptor. Thus, the acquisition of potentially disease-inducing <i>Mtvs</i> is a recent and ongoing process in <i>Mus</i> accompanied by recombination, positive selection, and a recurrent envelope deletion.</p><p><strong>Importance: </strong>Endogenous retroviruses (ERVs) are copies of viral genomes inserted into host chromosomes, producing a fossil record of past infections and virus-host co-adaptations. ERVs of mouse mammary tumor viruses (<i>Mtvs</i>) were found in all common laboratory strains, all <i>Mus musculus</i> subspecies, and a sister species, <i>Mus spretus</i>. Most laboratory mouse <i>Mtvs</i> predate inbred strain origins and were acquired by <i>M. musculus domesticus</i>, but although widely shared among strains, none of these were found in wild mice. Among wild mouse <i>Mtvs</i>, only one showed a broad geographic distribution. All <i>M. musculus</i> subspecies carry <i>Mtvs</i> with a large envelope deletion corresponding to the processed mRNA for the viral <i>rem</i> gene; such <i>Mtvs</i> likely derive from spliced viral mRNA. The <i>Mtv sag</i> gene responsible for resistance to exogenous infection is under purifying selection and has been subject to recombination, whereas the <i>Mtv</i> envelope and its cellular receptor show no evidence of genetic conflicts.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0007925"},"PeriodicalIF":4.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625011","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}