PLoS PathogensPub Date : 2024-11-19DOI: 10.1371/journal.ppat.1012709
Mathias Franzén Boger, Tyra Hasselrot, Vilde Kaldhusdal, Gisele H B Miranda, Paulo Czarnewski, Gabriella Edfeldt, Frideborg Bradley, Genta Rexaj, Julie Lajoie, Kenneth Omollo, Joshua Kimani, Keith R Fowke, Kristina Broliden, Annelie Tjernlund
{"title":"Sustained immune activation and impaired epithelial barrier integrity in the ectocervix of women with chronic HIV infection.","authors":"Mathias Franzén Boger, Tyra Hasselrot, Vilde Kaldhusdal, Gisele H B Miranda, Paulo Czarnewski, Gabriella Edfeldt, Frideborg Bradley, Genta Rexaj, Julie Lajoie, Kenneth Omollo, Joshua Kimani, Keith R Fowke, Kristina Broliden, Annelie Tjernlund","doi":"10.1371/journal.ppat.1012709","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012709","url":null,"abstract":"<p><p>Chronic systemic immune activation significantly influences human immunodeficiency virus (HIV) disease progression. Despite evidence of a pro-inflammatory environment in the genital tract of HIV-infected women, comprehensive investigations into cervical tissue from this region remain limited. Similarly, the consequences of chronic HIV infection on the integrity of the female genital epithelium are poorly understood, despite its importance in HIV transmission and replication. Ectocervical biopsies were obtained from HIV-seropositive (n = 14) and HIV-seronegative (n = 47) female Kenyan sex workers. RNA sequencing and bioimage analysis of epithelial junction proteins (E-cadherin, desmoglein-1, claudin-1, and zonula occludens-1) were conducted, along with CD4 staining. RNA sequencing revealed upregulation of immunoregulatory genes in HIV-seropositive women, primarily associated with heightened T cell activity and interferon signaling, which further correlated with plasma viral load. Transcription factor analysis confirmed the upregulation of pro-inflammatory transcription factors, such as RELA, NFKB1, and IKZF3, which facilitates HIV persistence in T cells. Conversely, genes and pathways associated with epithelial barrier function and structure were downregulated in the context of HIV. Digital bioimage analysis corroborated these findings, revealing significant disruption of various epithelial junction proteins in ectocervical tissues of the HIV-seropositive women. Thus, chronic HIV infection associated with ectocervical inflammation, characterized by induced T cell responses and interferon signaling, coupled with epithelial disruption. These alterations may influence HIV transmission and heighten susceptibility to other sexually transmitted infections. These findings prompt exploration of therapeutic interventions to address HIV-related complications and mitigate the risk of sexually transmitted infection transmission.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012709"},"PeriodicalIF":5.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677397","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":"Mucosal immunization with the lung Lactobacillus-derived amphiphilic exopolysaccharide adjuvanted recombinant vaccine improved protection against P. aeruginosa infection.","authors":"Haochi Zhang, Shouxin Sheng, Chunhe Li, Xuemei Bao, Lixia Zhao, Jian Chen, Pingyuan Guan, Xiaoyan Li, Na Pan, Yanchen Liang, Xueqi Wang, Jingmin Sun, Xiao Wang","doi":"10.1371/journal.ppat.1012696","DOIUrl":"10.1371/journal.ppat.1012696","url":null,"abstract":"<p><p>Respiratory infections caused by Pseudomonas aeruginosa are a major health problem globally. Current treatment for P. aeruginosa infections relies solely on antibiotics, but the rise of antibiotic-resistant strains necessitates an urgent need for a protective vaccine. Traditional parenteral vaccines, despite employing potent adjuvants aimed at serotype-dependent immunity, often fail to elicit the desired mucosal immune response. Thus, developing vaccines that target both localized mucosal and systemic immune responses represents a promising direction for future research on P. aeruginosa vaccination. In this study, we explored EPS301, the exopolysaccharide derived from the lung microbiota strain Lactobacillus plantarum WXD301, which exhibits excellent self-assembly properties, enabling the formation of homogeneous nanoparticles when encapsulating recombinant PcrV of P. aeruginosa, designated as EPS301@rPcrV. Notably, the EPS301 vector effectively enhanced antigen adhesion to the nasal and pulmonary mucosal tissues and prolonged antigen retention. Moreover, EPS301@rPcrV provided effective and sustained protection against P. aeruginosa pneumonia, surpassing the durability achieved with the \"gold standard\" cholera toxin adjuvant. The EPS301-adjuvanted vaccine formulation elicited robust mucosal IgA and Th17/γδ17 T cell responses, which exceeded those induced by the CTB-adjuvanted vaccination and were sustained for over 112 days. Additionally, Th 17 and γδ 17 resident memory T cells induced by EPS301@rPcrV were crucial for protection against P. aeruginosa challenge. Intriguingly, IL-17A knockout mice exhibited lower survival rates, impaired bacterial clearance ability, and exacerbated lung tissue damage upon EPS301 adjuvanted vaccination against P. aeruginosa-induced pneumonia, indicating an IL-17A-dependent protective mechanism. In conclusion, our findings provided direct evidence that EPS301@rPcrV mucosal vaccine is a promising candidate for future clinical application against P. aeruginosa-induced pulmonary infection.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012696"},"PeriodicalIF":5.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669001","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}
PLoS PathogensPub Date : 2024-11-18DOI: 10.1371/journal.ppat.1012647
Kaori Oikawa, Koki Fujisaki, Motoki Shimizu, Takumi Takeda, Keiichiro Nemoto, Hiromasa Saitoh, Akiko Hirabuchi, Yukie Hiraka, Naomi Miyaji, Aleksandra Białas, Thorsten Langner, Ronny Kellner, Tolga O Bozkurt, Stella Cesari, Thomas Kroj, Mark J Banfield, Sophien Kamoun, Ryohei Terauchi
{"title":"The blast pathogen effector AVR-Pik binds and stabilizes rice heavy metal-associated (HMA) proteins to co-opt their function in immunity.","authors":"Kaori Oikawa, Koki Fujisaki, Motoki Shimizu, Takumi Takeda, Keiichiro Nemoto, Hiromasa Saitoh, Akiko Hirabuchi, Yukie Hiraka, Naomi Miyaji, Aleksandra Białas, Thorsten Langner, Ronny Kellner, Tolga O Bozkurt, Stella Cesari, Thomas Kroj, Mark J Banfield, Sophien Kamoun, Ryohei Terauchi","doi":"10.1371/journal.ppat.1012647","DOIUrl":"10.1371/journal.ppat.1012647","url":null,"abstract":"<p><p>Intracellular nucleotide-binding domain and leucine-rich repeat-containing (NLR) receptors play crucial roles in immunity across multiple domains of life. In plants, a subset of NLRs contain noncanonical integrated domains that are thought to have evolved from host targets of pathogen effectors to serve as pathogen baits. However, the functions of host proteins with similarity to NLR integrated domains and the extent to which they are targeted by pathogen effectors remain largely unknown. Here, we show that the blast fungus effector AVR-Pik binds a subset of related rice proteins containing a heavy metal-associated (HMA) domain, one of the domains that has repeatedly integrated into plant NLR immune receptors. We find that AVR-Pik binding stabilizes the rice small HMA (sHMA) proteins OsHIPP19 and OsHIPP20. Knockout of OsHIPP20 causes enhanced disease resistance towards the blast pathogen, indicating that OsHIPP20 is a susceptibility gene (S-gene). We propose that AVR-Pik has evolved to bind HMA domain proteins and co-opt their function to suppress immunity. Yet this binding carries a trade-off, it triggers immunity in plants carrying NLR receptors with integrated HMA domains.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012647"},"PeriodicalIF":5.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669028","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}
PLoS PathogensPub Date : 2024-11-18DOI: 10.1371/journal.ppat.1012711
Yazmin E Cruz-Pulido, Natalie J LoMascolo, Delaina May, Jomana Hatahet, Caroline E Thomas, Andrea K W Chu, Samantha P Stacey, Maria Del Mar Villanueva Guzman, Gregory Aubert, Bryan C Mounce
{"title":"Polyamines mediate cellular energetics and lipid metabolism through mitochondrial respiration to facilitate virus replication.","authors":"Yazmin E Cruz-Pulido, Natalie J LoMascolo, Delaina May, Jomana Hatahet, Caroline E Thomas, Andrea K W Chu, Samantha P Stacey, Maria Del Mar Villanueva Guzman, Gregory Aubert, Bryan C Mounce","doi":"10.1371/journal.ppat.1012711","DOIUrl":"10.1371/journal.ppat.1012711","url":null,"abstract":"<p><p>Polyamines are critical cellular components that regulate a variety of processes, including translation, cell cycling, and nucleic acid metabolism. The polyamines, putrescine, spermidine, and spermine, are found abundantly within cells and are positively-charged at physiological pH. Polyamine metabolism is connected to distinct other metabolic pathways, including nucleotide and amino acid metabolism. However, the breadth of the effect of polyamines on cellular metabolism remains to be fully understood. We recently demonstrated a role for polyamines in cholesterol metabolism, and following these studies, we measured the impact of polyamines on global lipid metabolism. We find that lipid droplets increase in number and size with polyamine depletion. We further demonstrate that lipid anabolism is markedly decreased, and lipid accumulation is due to reduced mitochondrial fatty acid oxidation. In fact, mitochondrial structure and function are largely ablated with polyamine depletion. To compensate, cells depleted of polyamines switch from aerobic respiration to glycolysis in a polyamine depletion-mediated Warburg-like effect. Finally, we show that inhibitors of lipid metabolism are broadly antiviral, suggesting that polyamines and lipids are promising antiviral targets. Together, these data demonstrate a novel role for polyamines in mitochondrial function, lipid metabolism, and cellular energetics.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012711"},"PeriodicalIF":5.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669034","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}
PLoS PathogensPub Date : 2024-11-18DOI: 10.1371/journal.ppat.1012700
Zhiwen Jiang, Andres Merits, Ying Qin, Gang Xing, Letian Zhang, Jie Chen, Ningning Wang, Margus Varjak, Xiaofeng Zhai, Dongyan Li, Wanjie Song, Shuo Su
{"title":"Attenuated Getah virus confers protection against multiple arthritogenic alphaviruses.","authors":"Zhiwen Jiang, Andres Merits, Ying Qin, Gang Xing, Letian Zhang, Jie Chen, Ningning Wang, Margus Varjak, Xiaofeng Zhai, Dongyan Li, Wanjie Song, Shuo Su","doi":"10.1371/journal.ppat.1012700","DOIUrl":"10.1371/journal.ppat.1012700","url":null,"abstract":"<p><p>Alphaviruses are important arthropod-transmitted pathogens of humans and livestock. Getah virus (GETV) is an arthritogenic alphavirus that causes disease in horses and piglets; it also poses a potential threat to humans. A live attenuated vaccine candidate named GETV-3ΔS2-CM1, harbouring a deletion in nonstructural protein 3 and substitutions in the capsid protein, is genetically stable and exhibits robust immunogenicity. It was shown to confer passive protection to piglets born to immunized sows. In mice, a single dose of GETV-3ΔS2-CM1 protected against infection with different strains of GETV, Semliki Forest virus, Ross River virus, o'nyong'nyong virus, chikungunya virus, and Barmah Forest virus. Chimaeras based on the GETV-3ΔS2-CM1 backbone maintained both the attenuated phenotype and high immunogenicity. The safety, efficacy, and ability to induce protection against multiple alphaviruses highlights the potential of GETV-3ΔS2-CM1 and chimaeras using this backbone as promising vaccine candidates. By contributing simultaneously to the wellbeing of animals and humans, our universal next generation vaccine strategy helps to achieve \"One Health\" goals.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012700"},"PeriodicalIF":5.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668947","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}
PLoS PathogensPub Date : 2024-11-18DOI: 10.1371/journal.ppat.1012724
Jeffrey Seow, George C E Jefferson, Michael D Keegan, Yeuk Yau, Luke B Snell, Katie J Doores
{"title":"Profiling serum immunodominance following SARS-CoV-2 primary and breakthrough infection reveals distinct variant-specific epitope usage and immune imprinting.","authors":"Jeffrey Seow, George C E Jefferson, Michael D Keegan, Yeuk Yau, Luke B Snell, Katie J Doores","doi":"10.1371/journal.ppat.1012724","DOIUrl":"10.1371/journal.ppat.1012724","url":null,"abstract":"<p><p>Over the course of the COVID-19 pandemic, variants have emerged with increased mutations and immune evasive capabilities. This has led to breakthrough infections (BTI) in vaccinated individuals, with a large proportion of the neutralizing antibody response targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike glycoprotein. Immune imprinting, where prior exposure of the immune system to an antigen can influence the response to subsequent exposures, and its role in a population with heterogenous exposure histories has important implications in future vaccine design. Here, we develop an accessible approach to map epitope immunodominance of the neutralizing antibody response in sera. By using a panel of mutant Spike proteins in a pseudotyped virus neutralization assay, we observed distinct epitope usage in convalescent donors infected during wave 1, or infected with the Delta, or BA.1 variants, highlighting the antigenic diversity of the variant Spikes. Analysis of longitudinal serum samples taken spanning 3 doses of COVID-19 vaccine and subsequent breakthrough infection, showed the influence of immune imprinting from the ancestral-based vaccine, where reactivation of existing B cells elicited by the vaccine resulted in the enrichment of the pre-existing epitope immunodominance. However, subtle shifts in epitope usage in sera were observed following BTI by Omicron sub-lineage variants. Antigenic distance of Spike, time after last exposure, and number of vaccine boosters may play a role in the persistence of imprinting from the vaccine. This study provides insight into RBD neutralizing epitope usage in individuals with varying exposure histories and has implications for design of future SARS-CoV-2 vaccines.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012724"},"PeriodicalIF":5.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669038","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}
PLoS PathogensPub Date : 2024-11-15DOI: 10.1371/journal.ppat.1012704
Alexandra L Tse, Cory M Acreman, Inna Ricardo-Lax, Jacob Berrigan, Gorka Lasso, Toheeb Balogun, Fiona L Kearns, Lorenzo Casalino, Georgia L McClain, Amartya Mudry Chandran, Charlotte Lemeunier, Rommie E Amaro, Charles M Rice, Rohit K Jangra, Jason S McLellan, Kartik Chandran, Emily Happy Miller
{"title":"Distinct pathways for evolution of enhanced receptor binding and cell entry in SARS-like bat coronaviruses.","authors":"Alexandra L Tse, Cory M Acreman, Inna Ricardo-Lax, Jacob Berrigan, Gorka Lasso, Toheeb Balogun, Fiona L Kearns, Lorenzo Casalino, Georgia L McClain, Amartya Mudry Chandran, Charlotte Lemeunier, Rommie E Amaro, Charles M Rice, Rohit K Jangra, Jason S McLellan, Kartik Chandran, Emily Happy Miller","doi":"10.1371/journal.ppat.1012704","DOIUrl":"10.1371/journal.ppat.1012704","url":null,"abstract":"<p><p>Understanding the zoonotic risks posed by bat coronaviruses (CoVs) is critical for pandemic preparedness. Herein, we generated recombinant vesicular stomatitis viruses (rVSVs) bearing spikes from divergent bat CoVs to investigate their cell entry mechanisms. Unexpectedly, the successful recovery of rVSVs bearing the spike from SHC014-CoV, a SARS-like bat CoV, was associated with the acquisition of a novel substitution in the S2 fusion peptide-proximal region (FPPR). This substitution enhanced viral entry in both VSV and coronavirus contexts by increasing the availability of the spike receptor-binding domain to recognize its cellular receptor, ACE2. A second substitution in the S1 N-terminal domain, uncovered through the rescue and serial passage of a virus bearing the FPPR substitution, further enhanced spike:ACE2 interaction and viral entry. Our findings identify genetic pathways for adaptation by bat CoVs during spillover and host-to-host transmission, fitness trade-offs inherent to these pathways, and potential Achilles' heels that could be targeted with countermeasures.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012704"},"PeriodicalIF":5.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639994","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}
PLoS PathogensPub Date : 2024-11-15DOI: 10.1371/journal.ppat.1012118
Silke Malmsheimer, Iwan Grin, Erwin Bohn, Mirita Franz-Wachtel, Boris Macek, Tobias Sahr, Fabian Smollich, David Chetrit, Amit Meir, Craig Roy, Carmen Buchrieser, Samuel Wagner
{"title":"The T4bSS of Legionella features a two-step secretion pathway with an inner membrane intermediate for secretion of transmembrane effectors.","authors":"Silke Malmsheimer, Iwan Grin, Erwin Bohn, Mirita Franz-Wachtel, Boris Macek, Tobias Sahr, Fabian Smollich, David Chetrit, Amit Meir, Craig Roy, Carmen Buchrieser, Samuel Wagner","doi":"10.1371/journal.ppat.1012118","DOIUrl":"10.1371/journal.ppat.1012118","url":null,"abstract":"<p><p>To promote intracellular survival and infection, Legionella spp. translocate hundreds of effector proteins into eukaryotic host cells using a type IV b protein secretion system (T4bSS). T4bSS are well known to translocate soluble as well as transmembrane domain-containing effector proteins (TMD-effectors) but the mechanisms of secretion are still poorly understood. Herein we investigated the secretion of hydrophobic TMD-effectors, of which about 80 were previously reported to be encoded by L. pneumophila. A proteomic analysis of fractionated membranes revealed that TMD-effectors are targeted to and inserted into the bacterial inner membranes of L. pneumophila independent of the presence of a functional T4bSS. While the T4bSS chaperones IcmS and IcmW were critical for secretion of all tested TMD-effectors, they did not influence inner membrane targeting of these proteins. As for soluble effector proteins, translocation of all investigated TMD-effectors depended on a C-terminal secretion signal. A deeper analysis of the TMD-effector SidF showed that this signal needed to be presented towards the cytoplasmic side of the inner membrane and that a small periplasmic loop was required for efficient translocation. We propose that strongly hydrophobic TMD-effectors are secreted in a two-step secretion process: Initially, an inner membrane intermediate is formed, that is extracted towards the cytoplasmic side, possibly by the help of the type IV coupling protein complex and subsequently secreted into eukaryotic host cells by the T4bSS core complex. Overall, our study highlights the amazing versatility of T4bSS to secrete soluble and TMD-effectors from different subcellular locations of the bacterial cell.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012118"},"PeriodicalIF":5.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640003","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":"NS1-mediated DNMT1 degradation regulates human bocavirus 1 replication and RNA processing.","authors":"Shuangkang Qin, Honghe Chen, Chuchu Tian, Zhen Chen, Li Zuo, Xueyan Zhang, Haojie Hao, Fang Huang, Haibin Liu, Xiulian Sun, Wuxiang Guan","doi":"10.1371/journal.ppat.1012682","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012682","url":null,"abstract":"<p><p>Methylation of the DNA genome plays an important role in viral gene inactivation. However, the role of DNA methylation in human bocavirus (HBoV) remains unclear. In this study, the HBoV1 genomic DNA was found extensively methylated at the CHG and CHH sites. Inhibiting DNA methylation with 5-aza-2'-deoxycytidine (DAC) altered the methylation status and reduced viral DNA production, while enhanced the RNA splicing at D1 and D3 sites and the polyadenylation at the proximal polyadenylation site, (pA)p. Knockdown of DNA methyltransferase 1 (DNMT1) had the same effect on viral DNA synthesis and RNA processing as the DAC treatment, indicating that DNMT1 is the major host methyltransferase involved in viral DNA methylation. In addition, the nonstructural protein NS1 promoted DNMT1 degradation through the ubiquitin-proteasome pathway to regulate viral replication and RNA processing. Collectively, the results suggest that DNA methylation and DNMT1 facilitate HBoV replication and are essential for appropriate NS1 localization in the nucleus. DNMT1 degradation through NS1 promotes the virus RNA processing, leading to viral protein expression.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012682"},"PeriodicalIF":5.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630380","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}
PLoS PathogensPub Date : 2024-11-14DOI: 10.1371/journal.ppat.1012688
Rebekah A Jones, Fidel Ramirez-Bencomo, Gail Whiting, Min Fang, Hayley Lavender, Kacper Kurzyp, Angela Thistlethwaite, Lenka Stejskal, Smruti Rashmi, Ann E Jerse, Ana Cehovin, Jeremy P Derrick, Christoph M Tang
{"title":"Tackling immunosuppression by Neisseria gonorrhoeae to facilitate vaccine design.","authors":"Rebekah A Jones, Fidel Ramirez-Bencomo, Gail Whiting, Min Fang, Hayley Lavender, Kacper Kurzyp, Angela Thistlethwaite, Lenka Stejskal, Smruti Rashmi, Ann E Jerse, Ana Cehovin, Jeremy P Derrick, Christoph M Tang","doi":"10.1371/journal.ppat.1012688","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012688","url":null,"abstract":"<p><p>Gonorrhoea, caused by Neisseria gonorrhoeae, is a common sexually transmitted infection. Increasing multi-drug resistance and the impact of asymptomatic infections on sexual and reproductive health underline the need for an effective gonococcal vaccine. Outer membrane vesicles (OMVs) from Neisseria meningitidis induce modest cross-protection against gonococcal infection. However, the presence of proteins in OMVs derived from N. gonorrhoeae that manipulate immune responses could hamper their success as a vaccine. Here we modified two key immunomodulatory proteins of the gonococcus; RmpM, which can elicit 'blocking antibodies', and PorB, an outer membrane porin which contributes to immunosuppression. As meningococcal PorB has adjuvant properties, we replaced gonococcal PorB with a meningococcal PorB. Immunisation with OMVs from N. gonorrhoeae lacking rmpM and expressing meningococcal porB elicited higher antibody titres against model antigens in mice compared to OMVs with native PorB. Further, a gonococcal protein microarray revealed stronger IgG antibody responses to a more diverse range of antigens in the Nm PorB OMV immunised group. Finally, meningococcal PorB OMVs resulted in a Th1-skewed response, exemplified by increased serum IgG2a antibody responses and increased IFNɣ production by splenocytes from immunised mice. In summary, we demonstrate that the replacement of PorB in gonococcal OMVs enhances immune responses and offers a strategy for gonococcal vaccine development.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 11","pages":"e1012688"},"PeriodicalIF":5.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142636185","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}