PLoS Pathogens最新文献

{"title":"Hepatitis B virus hijacks MRE11-RAD50-NBS1 complex to form its minichromosome.","authors":"Kaitao Zhao, Jingjing Wang, Zichen Wang, Mengfei Wang, Chen Li, Zaichao Xu, Qiong Zhan, Fangteng Guo, Xiaoming Cheng, Yuchen Xia","doi":"10.1371/journal.ppat.1012824","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012824","url":null,"abstract":"<p><p>Chronic hepatitis B virus (HBV) infection can significantly increase the incidence of cirrhosis and liver cancer, and there is no curative treatment. The persistence of HBV covalently closed circular DNA (cccDNA) is the major obstacle of antiviral treatments. cccDNA is formed through repairing viral partially double-stranded relaxed circular DNA (rcDNA) by varies host factors. However, the detailed mechanisms are not well characterized. To dissect the biogenesis of cccDNA, we took advantage of an in vitro rcDNA repair system to precipitate host factors interacting with rcDNA and identified co-precipitated proteins by mass spectrometry. Results revealed the MRE11-RAD50-NBS1 (MRN) complex as a potential factor. Transiently or stably knockdown of MRE11, RAD50 or NBS1 in hepatocytes before HBV infection significantly decreased viral markers, including cccDNA, while reconstitution reversed the effect. Chromatin immunoprecipitation assay further validated the interaction of MRN complex and HBV DNA. However, MRN knockdown after HBV infection showed no effect on viral replication, which indicated that MRN complex inhibited the formation of cccDNA without affecting its stability or transcriptional activity. Interestingly, Mirin, a MRN complex inhibitor which can inhibit the exonuclease activity of MRE11 and MRN-dependent activation of ATM, but not ATM kinase inhibitor KU55933, could decrease cccDNA level. Likewise, the MRE11 endonuclease activity inhibitor PFM01 treatment decreased cccDNA. MRE11 nuclease assays indicated that rcDNA is a substrate of MRE11. Furthermore, the inhibition of ATR-CHK1 pathway, which is known to be involved in cccDNA formation, impaired the effect of MRN complex on cccDNA. Similarly, inhibition of MRE11 endonuclease activity mitigated the effect of ATR-CHK1 pathway on cccDNA. These findings indicate that MRN complex cooperates with ATR-CHK1 pathway to regulate the formation of HBV cccDNA. In summary, we identified host factors, specifically the MRN complex, regulating cccDNA formation during HBV infection. These findings provide insights into how HBV hijacks host enzymes to establish chronic infection and reveal new therapeutic opportunities.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012824"},"PeriodicalIF":5.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small interfering RNAs generated from the terminal panhandle structure of negative-strand RNA virus promote viral infection.","authors":"Wan Zhao, Qiong Li, Mengqi Sun, Lan Luo, Xiaoming Zhang, Feng Cui","doi":"10.1371/journal.ppat.1012789","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012789","url":null,"abstract":"<p><p>Virus-derived small interfering RNAs (vsiRNAs) have been widely recognized to play an antiviral immunity role. However, it is unclear whether vsiRNAs can also play a positive role in viral infection. Here, we characterized three highly abundant vsiRNAs mapped to the genomic termini of rice stripe virus (RSV), a negative-strand RNA virus transmitted by insect vectors. The three vsiRNAs shared 11 nucleotides due to the conservative genomic termini and were likely generated from viral terminal panhandle structure, depending on both Dicer1 and Dicer2 in insects. In addition to targeting viral RNAs in a miRNA-like manner, the three vsiRNAs coordinately downregulated the expression of DOPA decarboxylase, thereby suppressing the prophenoloxidase immune reaction in insect vectors. In vsiRNA-silenced transgenic rice, the viral titer significantly decreased, indicating that these vsiRNAs promote RSV replication in rice. This study elucidates a unique function of vsiRNAs derived from the conserved panhandle structure of negative-strand RNA viruses in enhancing viral infection.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012789"},"PeriodicalIF":5.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Manganese is a potent inducer of lysosomal activity that inhibits de novo HBV infection.","authors":"Lin Yu, Hao Chang, Wentao Xie, Yuan Zheng, Le Yang, Qiong Wu, Fan Bu, Yuanfei Zhu, Youhua Xie, Guoyu Pan, Ke Lan, Qiang Deng","doi":"10.1371/journal.ppat.1012800","DOIUrl":"10.1371/journal.ppat.1012800","url":null,"abstract":"<p><p>Sodium taurocholate co-transporting polypeptide (NTCP) has been identified as an entry receptor for hepatitis B virus (HBV), but the molecular events of the viral post-endocytosis steps remain obscure. In this study, we discovered that manganese (Mn) could strongly inhibit HBV infection in NTCP-reconstituted HepG2 cells without affecting viral replication. We therefore profiled the antiviral effects of Mn2+ in an attempt to elucidate the regulatory mechanisms involved in early HBV infection. Intriguingly, Mn2+ conspicuously stimulated lysosomal activity, as evidenced by hyperactivation of mTORC1 and increased endo/lysosomal acidity. After HBV-triggered internalization, the NTCP receptor was sorted to late endosomal compartments by the ESCRT machinery in concert with the invading virion. The establishment of HBV infection was found to be independent of lysosomal fusion-driven late endosome maturation; Mn2+-induced lysosomal hyperfunction virtually impaired infection, suggesting that virions may gain cytosolic access directly from late endosomes. In contrast, suppression of lysosomal activity substantially enhanced HBV infection. Prolonged mTORC1 inactivation facilitated viral infection by depleting lysosomes and accelerating endocytic transport of virions. Notably, treatment with the natural steroidal alkaloid tomatidine recapitulated the effects of Mn2+ in stimulating lysosomal activity and exhibited potent anti-HBV activity in HepG2-NTCP cells and in proliferating human hepatocyte organoids. These findings provide new insights into the post-endocytosis events of HBV infection. The negative regulation of early HBV infection by endo/lysosomal activity makes it a promising target for antiviral therapies.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012800"},"PeriodicalIF":5.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic interplay of autophagy and membrane repair during Mycobacterium tuberculosis Infection.","authors":"Jacques Augenstreich, Anna T Phan, Charles N S Allen, Anushka Poddar, Hanzhang Chen, Lalitha Srinivasan, Volker Briken","doi":"10.1371/journal.ppat.1012830","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012830","url":null,"abstract":"<p><p>Autophagy plays a crucial role in the host response to Mycobacterium tuberculosis (Mtb) infection, yet the dynamics and regulation of autophagy induction on Mtb-containing vacuoles (MCVs) remain only partially understood. We employed time-lapse confocal microscopy to investigate the recruitment of LC3B (LC3), a key autophagy marker, to MCVs at the single cell level with our newly developed workflow for single cell and single MCV tracking and fluorescence quantification. We show that approximately 70% of MCVs exhibited LC3 recruitment but that was lost in about 40% of those MCVs. The LC3 recruitment to MCVs displayed a high variability in timing that was independent of the size of the MCV or the bacterial burden. Most notably, the LC3-positive MCVs did not acidify, indicating that LC3 recruitment does not necessarily lead to the formation of mature autophagolysosomes. Interferon-gamma pre-treatment did not affect LC3 recruitment frequency or autophagosome acidification but increased the susceptibility of the macrophage to Mtb-induced cell death. LC3 recruitment and lysotracker staining were mutually exclusive events, alternating on some MCVs multiple times thus demonstrating a reversible aspect of the autophagy response. The LC3 recruitment was associated with galectin-3 and oxysterol-binding protein 1 staining, indicating a correlation with membrane damage and repair mechanisms. ATG7 knock-down did not impact membrane repair, suggesting that autophagy is not directly involved in this process but is coregulated by the membrane damage of MCVs. In summary, our findings provide novel insights into the dynamic and variable nature of LC3 recruitment to the MCVs over time during Mtb infection. Our data does not support a role for autophagy in either cell-autonomous defense against Mtb or membrane repair of the MCV in human macrophages. In addition, the combined dynamics of LC3 recruitment and Lysoview staining emerged as promising markers for investigating the damage and repair processes of phagosomal membranes.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 1","pages":"e1012830"},"PeriodicalIF":5.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential contribution of PBP occupancy and efflux on the effectiveness of β-lactams at their target site in clinical isolates of Neisseria gonorrhoeae.","authors":"Silvia López-Argüello, Eva Alcoceba, Paula Ordóñez, Biel Taltavull, Gabriel Cabot, Maria Antonia Gomis-Font, Antonio Oliver, Bartolome Moya","doi":"10.1371/journal.ppat.1012783","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012783","url":null,"abstract":"<p><p>Neisseria gonorrhoeae exhibits alarming antibiotic resistance trends and poses a significant challenge in therapeutic management. This study aimed to explore the association of penA alleles with penicillin-binding protein (PBP) occupancy patterns and reduced outer membrane permeability, impacting susceptibility to last-line cephalosporins and potential β-lactam candidates. The whole genome sequence, the MICs and PBP IC50s were determined for 12 β-lactams and β-lactamase inhibitors in 8 clinical isolates with varying β-lactam sensitivity, 2 ATCC, and 3 WHO cephalosporin-resistant reference strains. The genetic analysis identified diverse determinants of β-lactam resistance including penA, ponA, porB, and mtrR alterations. Mosaic penA alleles were confirmed to be key determinants of cephalosporin resistance, with notable impacts on PBP2 IC50 affinities (in the presence of all PBPs). Substitutions in positions V316 and A501 exhibited significant effects on β-lactam PBP2 occupancy and MICs. PBP1 inhibition showed marginal effect on β-lactam sensitivity and PBP3 acted as a sink target. Ertapenem and piperacillin emerged as potential therapies against cephalosporin-resistant N. gonorrhoeae strains, along with combination therapies involving tazobactam and/or efflux inhibitors. The study determined the β-lactam PBP-binding affinities of last-line cephalosporins and alternative β-lactam candidates in strains carrying different penA alleles for the first time. These findings provide insights for developing new antimicrobial agents and enhancers against emerging resistant strains. Further research is warranted to optimize therapeutic interventions for cephalosporin-resistant N. gonorrhoeae infections.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012783"},"PeriodicalIF":5.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIV-1 exploits LBPA-dependent intraepithelial trafficking for productive infection of human intestinal mucosa.","authors":"Anusca G Rader, Alexandra P M Cloherty, Kharishma S Patel, Dima D A Almandawi, Dasja Pajkrt, Katja C Wolthers, Adithya Sridhar, Sterre van Piggelen, Liselotte E Baaij, Renée R C E Schreurs, Carla M S Ribeiro","doi":"10.1371/journal.ppat.1012714","DOIUrl":"10.1371/journal.ppat.1012714","url":null,"abstract":"<p><p>The gastrointestinal tract is a prominent portal of entry for HIV-1 during sexual or perinatal transmission, as well as a major site of HIV-1 persistence and replication. Elucidation of underlying mechanisms of intestinal HIV-1 infection are thus needed for the advancement of HIV-1 curative therapies. Here, we present a human 2D intestinal immuno-organoid system to model HIV-1 disease that recapitulates tissue compartmentalization and epithelial-immune cellular interactions. Our data demonstrate that apical exposure of intestinal epithelium to HIV-1 results in viral internalization, with subsequent basolateral shedding of replication-competent viruses, in a manner that is impervious to antiretroviral treatment. Incorporation of subepithelial dendritic cells resulted in HIV-1 luminal sampling and amplification of residual viral replication of lab-adapted and transmitted-founder (T/F) HIV-1 variants. Markedly, intraepithelial viral capture ensued an altered distribution of specialized endosomal pathways alongside durable sequestration of infectious HIV-1 within lysobisphosphatidic acid (LPBA)-rich vesicles. Therapeutic neutralization of LBPA-dependent trafficking limited productive HIV-1 infection, and thereby demonstrated the pivotal role of intraepithelial multivesicular endosomes as niches for virulent HIV-1 within the intestinal mucosa. Our study showcases the application of primary human 2D immune-competent organoid cultures in uncovering mechanisms of intestinal HIV-1 disease as well as a platform for preclinical antiviral drug discovery.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012714"},"PeriodicalIF":5.5,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11676502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternative splicing expands the antiviral IFITM repertoire in Chinese rufous horseshoe bats.","authors":"Nelly S C Mak, Jingyan Liu, Dan Zhang, Jordan Taylor, Xiaomeng Li, Kazi Rahman, Feiyu Chen, Siddhartha A K Datta, Kin Kui Lai, Zhengli Shi, Nigel Temperton, Aaron T Irving, Alex A Compton, Richard D Sloan","doi":"10.1371/journal.ppat.1012763","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012763","url":null,"abstract":"<p><p>Species-specific interferon responses are shaped by the virus-host arms race. The human interferon-induced transmembrane protein (IFITM) family consists of three antiviral IFITM genes that arose by gene duplication. These genes restrict virus entry and are key players in antiviral interferon responses. The unique IFITM repertoires in different species influence their resistance to viral infections, but the role of IFITMs in shaping the enhanced antiviral immunity of reservoir bat species is unclear. Here, we identified an IFITM gene in Chinese rufous horseshoe bat, a natural host of severe acute respiratory syndrome (SARS)-related coronaviruses, that is alternatively spliced to produce two IFITM isoforms in native cells as shown by transcriptomics. These bat IFITMs have conserved structures in vitro as demonstrated by circular dichroism spectroscopy, yet they exhibit distinct antiviral specificities against influenza A virus, Nipah virus and coronaviruses including SARS-CoV, SARS-CoV-2 and MERS-CoV. In parallel with human IFITM1-3, bat IFITM isoforms localize to distinct sites of virus entry which influences their antiviral potency. Further bioinformatic analysis of IFITM repertoires in 206 mammals reveals that alternative splicing is a recurring strategy for IFITM diversification, albeit less widely adopted than gene duplication. These findings demonstrate that alternative splicing is a key strategy for evolutionary diversification in the IFITM family. Our study also highlights an example of convergent evolution where species-specific selection pressures led to expansion of the IFITM family through multiple means, underscoring the importance of IFITM diversity as a component of innate immunity.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012763"},"PeriodicalIF":5.5,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of sterilizing immunity provided by an HIV-1 neutralizing antibody against mucosal infection.","authors":"Elie Richel, Arne Cordsmeier, Larissa Bauer, Kirsten Fraedrich, Ramona Vestweber, Berit Roshani, Nicole Stolte-Leeb, Armin Ensser, Christiane Stahl-Hennig, Klaus Überla","doi":"10.1371/journal.ppat.1012777","DOIUrl":"10.1371/journal.ppat.1012777","url":null,"abstract":"<p><p>Broadly neutralizing antibodies (bnAbs) against HIV-1 have been shown to protect from systemic infection. When employing a novel challenge virus that uses HIV-1 Env for entry into target cells during the first replication cycle, but then switches to SIV Env usage, we demonstrated that bnAbs also prevented mucosal infection of the first cells. However, it remained unclear whether antibody Fc-effector functions contribute to this sterilizing immunity. Therefore, additional challenge viruses were produced that contain SIV Env and graded doses of a fusion-defective trimer of HIV-1 Env, to which the bnAb, PGT121 can bind without interfering with the SIV Env-based cell entry. After administration of either PGT121 or its mutant deficient in Fc-effector functions, rhesus macaques were intrarectally exposed to these challenge viruses and to those using either HIV-1 Env or SIV Env for entry into the first cells. Both antibodies similarly reduced infection events with the challenge virus using HIV-1 Env by a factor close to 200. Incorporating fusion-defective HIV-1 Env trimers into the particles of the challenge viruses at densities observed in primary virus isolates did not reduce SIV Env-mediated infection events. The results indicate that the sparsity of bnAb binding-sites on HIV-1 virions limits the contribution of Fc-effector functions to provide sterilizing immunity against mucosal viral infection. Hence, harnessing Fc-effector functions for sterilizing immunity against mucosal HIV-1 infection may require strategies to increase the degree of antibody opsonization.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012777"},"PeriodicalIF":5.5,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Ralstonia solanacearum type III effector alters the actin and microtubule cytoskeleton to promote bacterial virulence in plants.","authors":"Rachel Hiles, Abigail Rogers, Namrata Jaiswal, Weiwei Zhang, Jules Butchacas, Marcus V Merfa, Taylor Klass, Pragya Barua, Venkatesh P Thirumalaikumar, Jonathan M Jacobs, Christopher J Staiger, Matthew Helm, Anjali S Iyer-Pascuzzi","doi":"10.1371/journal.ppat.1012814","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012814","url":null,"abstract":"<p><p>Cellular responses to biotic stress frequently involve signaling pathways that are conserved across eukaryotes. These pathways include the cytoskeleton, a proteinaceous network that senses external cues at the cell surface and signals to interior cellular components. During biotic stress, dynamic cytoskeletal rearrangements serve as a platform from which early immune-associated processes are organized and activated. Bacterial pathogens of plants and animals use proteins called type III effectors (T3Es) to interfere with host immune signaling, thereby promoting virulence. We previously found that RipU, a T3E from the soilborne phytobacterial pathogen Ralstonia solanacearum, co-localizes with the plant cytoskeleton. Here, we show that RipU from R. solanacearum K60 (RipUK60) associated with and altered the organization of both the actin and microtubule cytoskeleton. We found that pharmacological disruption of the tomato (Solanum lycopersicum) cytoskeleton promoted R. solanacearum K60 colonization. Importantly, tomato plants inoculated with R. solanacearum K60 lacking RipUK60 (ΔripUK60) had reduced wilting symptoms and significantly reduced root colonization when compared to plants inoculated with wild-type R. solanacearum K60. Collectively, our data suggest that R. solanacearum K60 uses the type III effector RipUK60 to remodel cytoskeletal organization, thereby promoting pathogen virulence.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012814"},"PeriodicalIF":5.5,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The SpxA1-TenA toxin-antitoxin system regulates epigenetic variations of Streptococcus pneumoniae by targeting protein synthesis.","authors":"Shaomeng Wang, Xiu-Yuan Li, Mengran Zhu, Haiteng Deng, Juanjuan Wang, Jing-Ren Zhang","doi":"10.1371/journal.ppat.1012801","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012801","url":null,"abstract":"<p><p>Human pathogen Streptococcus pneumoniae forms multiple epigenetically and phenotypically distinct intra-populations by invertase PsrA-driven inversions of DNA methyltransferase hsdS genes in the colony opacity-determinant (cod) locus. As manifested by phase switch between opaque and transparent colonies, different genome methylation patterns or epigenomes confer pathogenesis-associated traits, but it is unknown how the pathogen controls the hsdS inversion orientations. Here, we report our finding of the SpxA1-TenA toxin-antitoxin (TA) system that regulates the orientations of hsdS inversions, and thereby bacterial epigenome and associated traits (e.g., colony opacity) by targeting pneumococcal protein synthesis. SpxA1 and TenA were found to constitute a highly conserved type II TA system in S. pneumoniae, primarily based on the observation that overexpressing toxin TenA led to growth arrest in E. coli and enhanced autolysis in S. pneumoniae, and the antitoxin SpxA1 repressed the transcription of the spxA1-tenA operon. When the transcription of tenA was de-repressed by a spontaneous AT di-nucleotide insertion/deletion in the promoter region of the spxA1-tenA operon, TenA bound to the ribosome maturation factor RimM, and thereby reduced the cellular level of alternative sigma factor ComX (known for the activation of natural transformation-associated genes). Attenuation of ComX expression in turn enhanced the transcription of the invertase gene psrA, which favored the formation of the transparent colony phase-associated hsdS allelic configurations in the cod locus. Phenotypically, moderate expression of TenA dramatically reshaped pneumococcal epigenome and colony opacity. Because spontaneous variations frequently occur during bacterial growth in the number of the AT di-nucleotides in the promoter region of the spxA1-tenA operon, this locus acts as a programmed genetic switch that generates pneumococcal subpopulations with epigenetic and phenotypic diversity.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 12","pages":"e1012801"},"PeriodicalIF":5.5,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}