PLoS Pathogens最新文献_第2页

BiP/GRP78 is a pro-viral factor for diverse dsDNA viruses that promotes the survival and proliferation of cells upon KSHV infection. BiP/GRP78是多种dsDNA病毒的促病毒因子，在KSHV感染后可促进细胞的存活和增殖。

IF 5.5 1区医学

PLoS Pathogens Pub Date : 2024-10-29 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012660

Guillermo Najarro, Kevin Brackett, Hunter Woosley, Leah C Dorman, Vincent Turon-Lagot, Sudip Khadka, Catya Faeldonea, Osvaldo Kevin Moreno, Adriana Ramirez Negron, Christina Love, Ryan Ward, Charles Langelier, Frank McCarthy, Carlos Gonzalez, Joshua E Elias, Brooke M Gardner, Carolina Arias

{"title":"BiP/GRP78 is a pro-viral factor for diverse dsDNA viruses that promotes the survival and proliferation of cells upon KSHV infection.","authors":"Guillermo Najarro, Kevin Brackett, Hunter Woosley, Leah C Dorman, Vincent Turon-Lagot, Sudip Khadka, Catya Faeldonea, Osvaldo Kevin Moreno, Adriana Ramirez Negron, Christina Love, Ryan Ward, Charles Langelier, Frank McCarthy, Carlos Gonzalez, Joshua E Elias, Brooke M Gardner, Carolina Arias","doi":"10.1371/journal.ppat.1012660","DOIUrl":"10.1371/journal.ppat.1012660","url":null,"abstract":"The Endoplasmic Reticulum (ER)-resident HSP70 chaperone BiP (HSPA5) plays a crucial role in maintaining and restoring protein folding homeostasis in the ER. BiP's function is often dysregulated in cancer and virus-infected cells, conferring pro-oncogenic and pro-viral advantages. We explored BiP's functions during infection by the Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic gamma-herpesvirus associated with cancers of immunocompromised patients. Our findings reveal that BiP protein levels are upregulated in infected epithelial cells during the lytic phase of KSHV infection. This upregulation occurs independently of the unfolded protein response (UPR), a major signaling pathway that regulates BiP availability. Genetic and pharmacological inhibition of BiP halts KSHV viral replication and reduces the proliferation and survival of KSHV-infected cells. Notably, inhibition of BiP limits the spread of other alpha- and beta-herpesviruses and poxviruses with minimal toxicity for normal cells. Our work suggests that BiP is a potential target for developing broad-spectrum antiviral therapies against double-stranded DNA viruses and a promising candidate for therapeutic intervention in KSHV-related malignancies.","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11548844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548504","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}

引用次数: 0

The protein segregase VCP/p97 promotes host antifungal defense via regulation of SYK activation. 蛋白分离酶VCP/p97通过调节SYK活化促进宿主的抗真菌防御。

IF 5.5 1区医学

PLoS Pathogens Pub Date : 2024-10-29 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012674

Zhugui Shao, Li Wang, Limin Cao, Tian Chen, Xin-Ming Jia, Wanwei Sun, Chengjiang Gao, Hui Xiao

{"title":"The protein segregase VCP/p97 promotes host antifungal defense via regulation of SYK activation.","authors":"Zhugui Shao, Li Wang, Limin Cao, Tian Chen, Xin-Ming Jia, Wanwei Sun, Chengjiang Gao, Hui Xiao","doi":"10.1371/journal.ppat.1012674","DOIUrl":"10.1371/journal.ppat.1012674","url":null,"abstract":"C-type lectin receptors (CLRs) are essential to execute host defense against fungal infection. Nevertheless, a comprehensive understanding of the molecular underpinnings of CLR signaling remains a work in progress. Here, we searched for yet-to-be-identified tyrosine-phosphorylated proteins in Dectin-1 signaling and linked the stress-response protein valosin containing protein (VCP)/p97 to Dectin-1 signaling. Knockdown of VCP expression or chemical inhibition of VCP's segregase activity dampened Dectin-1-elicited SYK activation in BMDMs and BMDCs, leading to attenuated expression of proinflammatory cytokines/chemokines such as TNF-α, IL-6 and CXCL1. Biochemical analyses demonstrated that VCP and its cofactor UFD1 form a complex with SYK and its phosphatase SHP-1 following Dectin-1 ligation, and knockdown of VCP led to a more prominent SYK and SHP-1 association. Further, SHP-1 became polyubiquitinated upon Dectin-1 activation, and VCP or UFD1 overexpression accelerated SHP-1 degradation. Conceivably, VCP may promote Dectin-1 signaling by pulling the ubiquitinated SHP-1 out of the SYK complex for degradation. Finally, genetic ablation of VCP in the neutrophil and macrophage compartment rendered the mice highly susceptible to infection by Candida albicans, an observation also phenocopied by administering the VCP inhibitor. These results collectively demonstrate that VCP is a previously unappreciated signal transducer of the Dectin-1 pathway and a crucial component of antifungal defense, and suggest a new mechanism regulating SYK activation.","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11548748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548514","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}

引用次数: 0

A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants. 一种新型 4-氨基喹啉化学型，具有多级抗疟活性，且与 PfCRT 和 PfMDR1 突变体无交叉抗药性。

IF 5.5 1区医学

PLoS Pathogens Pub Date : 2024-10-29 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012627

Letícia Tiburcio Ferreira, Gustavo Capatti Cassiano, Luis Carlos Salazar Alvarez, John Okombo, Juliana Calit, Diana Fontinha, Eva Gil-Iturbe, Rachael Coyle, Carolina Horta Andrade, Per Sunnerhagen, Daniel Youssef Bargieri, Miguel Prudêncio, Matthias Quick, Pedro V Cravo, Marcus C S Lee, David A Fidock, Fabio Trindade Maranhão Costa

{"title":"A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants.","authors":"Letícia Tiburcio Ferreira, Gustavo Capatti Cassiano, Luis Carlos Salazar Alvarez, John Okombo, Juliana Calit, Diana Fontinha, Eva Gil-Iturbe, Rachael Coyle, Carolina Horta Andrade, Per Sunnerhagen, Daniel Youssef Bargieri, Miguel Prudêncio, Matthias Quick, Pedro V Cravo, Marcus C S Lee, David A Fidock, Fabio Trindade Maranhão Costa","doi":"10.1371/journal.ppat.1012627","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012627","url":null,"abstract":"Artemisinin-based combination therapy (ACT) is the mainstay of effective treatment of Plasmodium falciparum malaria. However, the long-term utility of ACTs is imperiled by widespread partial artemisinin resistance in Southeast Asia and its recent emergence in parts of East Africa. This underscores the need to identify chemotypes with new modes of action (MoAs) to circumvent resistance to ACTs. In this study, we characterized the asexual blood stage antiplasmodial activity and resistance mechanisms of LDT-623, a 4-aminoquinoline (4-AQ). We also detected LDT-623 activity against multiple stages (liver schizonts, stage IV-V gametocytes, and ookinetes) of Plasmodium's life cycle, a feature unlike other 4-AQs such as chloroquine (CQ) and piperaquine (PPQ). Using heme fractionation profiling and drug uptake studies in PfCRT-containing proteoliposomes, we observed inhibition of hemozoin formation and PfCRT-mediated transport, which constitute characteristic features of 4-AQs' MoA. We also found minimal cross-resistance to LDT-623 in a panel of mutant pfcrt or pfmdr1 lines, but not the PfCRT F145I mutant that is highly resistant to PPQ resistance yet is very unfit. No P. falciparum parasites were recovered in an in vitro resistance selection study, suggesting a high barrier for resistance to emerge. Finally, a competitive growth assay comprising >50 barcoded parasite lines with mutated resistance mediators or major drug targets found no evidence of cross-resistance. Our findings support further exploration of this promising 4-AQ.","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548503","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}

引用次数: 0

Balancing acts: The posttranslational modification tightrope of flavivirus replication. 平衡行为：黄病毒复制的翻译后修饰紧箍咒。

IF 5.5 1区医学

PLoS Pathogens Pub Date : 2024-10-28 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012626

RuthMabel Boytz, Maudry Laurent-Rolle

引用次数: 0

Porcine reproductive and respiratory syndrome virus nonstructural protein 2 promotes the autophagic degradation of adaptor protein SH3KBP1 to antagonize host innate immune responses by enhancing K63-linked polyubiquitination of RIG-I. 猪繁殖与呼吸综合征病毒非结构蛋白2促进适配蛋白SH3KBP1的自噬降解，通过增强RIG-I的K63连接多泛素化来拮抗宿主先天性免疫反应。

IF 5.5 1区医学

PLoS Pathogens Pub Date : 2024-10-28 DOI: 10.1371/journal.ppat.1012670

Jiaoyang Li, Jing Zhang, Pu Sun, Jian Wang, Guoxiu Li, Zhanding Cui, Dong Li, Hong Yuan, Tao Wang, Kun Li, Xingwen Bai, Zhixun Zhao, Yimei Cao, Xueqing Ma, Pinghua Li, Yuanfang Fu, Huifang Bao, Zaixin Liu, Shuqi Xiao, Xinglong Wang, Zengjun Lu

{"title":"Porcine reproductive and respiratory syndrome virus nonstructural protein 2 promotes the autophagic degradation of adaptor protein SH3KBP1 to antagonize host innate immune responses by enhancing K63-linked polyubiquitination of RIG-I.","authors":"Jiaoyang Li, Jing Zhang, Pu Sun, Jian Wang, Guoxiu Li, Zhanding Cui, Dong Li, Hong Yuan, Tao Wang, Kun Li, Xingwen Bai, Zhixun Zhao, Yimei Cao, Xueqing Ma, Pinghua Li, Yuanfang Fu, Huifang Bao, Zaixin Liu, Shuqi Xiao, Xinglong Wang, Zengjun Lu","doi":"10.1371/journal.ppat.1012670","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012670","url":null,"abstract":"Non-structural protein 2 (NSP2) of PRRSV is highly variable and plays crucial roles in the virus's life cycle. To elucidate the function of NSP2 during PRRSV infection, we identified SH3KBP1 as an NSP2-interacting host protein using mass spectrometry. Exogenous SH3KBP1 expression significantly inhibited PRRSV replication by enhancing IFN-I and related ISGs production. Conversely, SH3KBP1 knockdown promoted viral replication by downregulating IFN-I and ISGs levels. In vivo experiments revealed that Sh3kbp1-/- mice were more susceptible to VSV infection, exhibiting reduced serum IFN-β levels. Further investigation showed that SH3KBP1 enhances RIG-I signal transduction by increasing K63-linked polyubiquitination through interaction with the E3 ubiquitin ligase TRIM25. We also found that PRRSV infection and NSP2 overexpression induce the autophagic degradation of SH3KBP1, counteracting the host's innate immune response. A critical interaction site was identified within the third proline-rich motif in NSP2 (453PVPAPR458). Recombinant PRRSV lacking this motif displayed reduced virulence and decreased SH3KBP1 degradation. This study advances our understanding of how PRRSV interferes with the host immune response and offers valuable insights for development novel attenuated vaccines against PRRSV.","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523450","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}

引用次数: 0

Differences in phenotype between long-lived memory B cells against Plasmodium falciparum merozoite antigens and variant surface antigens. 针对恶性疟原虫虫体抗原和变体表面抗原的长效记忆 B 细胞的表型差异。

IF 5.5 1区医学

PLoS Pathogens Pub Date : 2024-10-28 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012661

Raphael A Reyes, Louise Turner, Isaac Ssewanyana, Prasanna Jagannathan, Margaret E Feeney, Thomas Lavstsen, Bryan Greenhouse, Sebastiaan Bol, Evelien M Bunnik

{"title":"Differences in phenotype between long-lived memory B cells against Plasmodium falciparum merozoite antigens and variant surface antigens.","authors":"Raphael A Reyes, Louise Turner, Isaac Ssewanyana, Prasanna Jagannathan, Margaret E Feeney, Thomas Lavstsen, Bryan Greenhouse, Sebastiaan Bol, Evelien M Bunnik","doi":"10.1371/journal.ppat.1012661","DOIUrl":"10.1371/journal.ppat.1012661","url":null,"abstract":"Plasmodium falciparum infections elicit strong humoral immune responses to two main groups of antigens expressed by blood-stage parasites: merozoite antigens that are involved in the erythrocyte invasion process and variant surface antigens that mediate endothelial sequestration of infected erythrocytes. Long-lived B cells against both antigen classes can be detected in the circulation for years after exposure, but have not been directly compared. Here, we studied the phenotype of long-lived memory and atypical B cells to merozoite antigens (MSP1 and AMA1) and variant surface antigens (the CIDRα1 domain of PfEMP1) in ten Ugandan adults before and after local reduction of P. falciparum transmission. After a median of 1.7 years without P. falciparum infections, the percentage of antigen-specific activated B cells declined, but long-lived antigen-specific B cells were still detectable in all individuals. The majority of MSP1/AMA1-specific B cells were CD95+CD11c+ memory B cells, which are primed for rapid differentiation into antibody-secreting cells, and FcRL5-T-bet- atypical B cells. On the other hand, most CIDRα1-specific B cells were CD95-CD11c- memory B cells. CIDRα1-specific B cells were also enriched among a subset of atypical B cells that seem poised for antigen presentation. These results point to differences in how these antigens are recognized or processed by the immune system and how P. falciparum-specific B cells will respond upon re-infection.","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523449","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}

引用次数: 0

Potent broadly neutralizing antibodies mediate efficient antibody-dependent phagocytosis of HIV-infected cells. 强效的广谱中和抗体介导了对艾滋病毒感染细胞的高效抗体依赖性吞噬作用。

IF 5.5 1区医学

PLoS Pathogens Pub Date : 2024-10-28 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012665

Brian J Snow, Nida K Keles, Michael W Grunst, Sanath Kumar Janaka, Ryan T Behrens, David T Evans

{"title":"Potent broadly neutralizing antibodies mediate efficient antibody-dependent phagocytosis of HIV-infected cells.","authors":"Brian J Snow, Nida K Keles, Michael W Grunst, Sanath Kumar Janaka, Ryan T Behrens, David T Evans","doi":"10.1371/journal.ppat.1012665","DOIUrl":"10.1371/journal.ppat.1012665","url":null,"abstract":"Antibody-dependent cellular phagocytosis (ADCP) has been implicated in protection against HIV-1. However, methods for measuring ADCP currently rely on the phagocytosis of gp120- or gp41-coated beads that do not reflect physiologically relevant conformations of the viral envelope glycoprotein or the size of a virus-infected cell. We therefore developed a novel approach for measuring ADCP of HIV-infected cells expressing natural conformations of Env. A monocytic cell line (THP-1 cells) or primary human monocytes were incubated with a CD4+ T cell line that expresses eGFP upon HIV-1 infection in the presence of antibodies and ADCP was measured as the accumulation of eGFP+ material by flow cytometry. The internalization of HIV-infected cells by monocytes was confirmed visually by image-capture flow cytometry. Cytoskeletal remodeling, pseudopod formation and phagocytosis were also observed by confocal microscopy. We found that potent broadly neutralizing antibodies (bnAbs), but not non-neutralizing antibodies (nnAbs), mediate efficient phagocytosis of cells infected with either primary or lab-adapted HIV-1. A nnAb to a CD4-inducible epitope of gp120 (A32) failed to enable ADCP of HIV-infected cells but mediated efficient phagocytosis of gp120-coated beads. Conversely, a bnAb specific to intact Env trimers (PGT145) mediated potent ADCP of HIV-infected cells but did not facilitate the uptake of gp120-coated beads. These results underscore the importance of measuring ADCP of HIV-infected cells expressing physiologically relevant conformations of Env and show that most antibodies that are capable of binding to Env trimers on virions to neutralize virus infectivity are also capable of binding to Env on the surface of virus-infected cells to mediate ADCP.","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523451","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}

引用次数: 0

Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses. 确定对 SARS-CoV-2、SARS-CoV-1 和相关沙棘病毒具有交叉反应性的抗体的功能活性。

IF 5.5 1区医学

PLoS Pathogens Pub Date : 2024-10-28 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012650

Felicitas Ruiz, William B Foreman, Michelle Lilly, Viren A Baharani, Delphine M Depierreux, Vrasha Chohan, Ashley L Taylor, Jamie Guenthoer, Duncan Ralph, Frederick A Matsen Iv, Helen Y Chu, Paul D Bieniasz, Marceline Côté, Tyler N Starr, Julie Overbaugh

{"title":"Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses.","authors":"Felicitas Ruiz, William B Foreman, Michelle Lilly, Viren A Baharani, Delphine M Depierreux, Vrasha Chohan, Ashley L Taylor, Jamie Guenthoer, Duncan Ralph, Frederick A Matsen Iv, Helen Y Chu, Paul D Bieniasz, Marceline Côté, Tyler N Starr, Julie Overbaugh","doi":"10.1371/journal.ppat.1012650","DOIUrl":"10.1371/journal.ppat.1012650","url":null,"abstract":"The recurring spillover of pathogenic coronaviruses and demonstrated capacity of sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need to better understand immune responses to this virus family. For this purpose, we characterized the functional breadth and potency of antibodies targeting the receptor binding domain (RBD) of the spike glycoprotein that exhibited cross-reactivity against SARS-CoV-2 variants, SARS-CoV-1 and sarbecoviruses from diverse clades and animal origins with spillover potential. One neutralizing antibody, C68.61, showed remarkable neutralization breadth against both SARS-CoV-2 variants and viruses from different sarbecovirus clades. C68.61, which targets a conserved RBD class 5 epitope, did not select for escape variants of SARS-CoV-2 or SARS-CoV-1 in culture nor have predicted escape variants among circulating SARS-CoV-2 strains, suggesting this epitope is functionally constrained. We identified 11 additional SARS-CoV-2/SARS-CoV-1 cross-reactive antibodies that target the more sequence conserved class 4 and class 5 epitopes within RBD that show activity against a subset of diverse sarbecoviruses with one antibody binding every single sarbecovirus RBD tested. A subset of these antibodies exhibited Fc-mediated effector functions as potent as antibodies that impact infection outcome in animal models. Thus, our study identified antibodies targeting conserved regions across SARS-CoV-2 variants and sarbecoviruses that may serve as therapeutics for pandemic preparedness as well as blueprints for the design of immunogens capable of eliciting cross-neutralizing responses.","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523448","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}

引用次数: 0

The full transcription map of cottontail rabbit papillomavirus in tumor tissues. 棉尾兔乳头状瘤病毒在肿瘤组织中的完整转录图。

IF 5.5 1区医学

PLoS Pathogens Pub Date : 2024-10-25 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012649

Pengfei Jiang, Vladimir Majerciak, Jiafen Hu, Karla Balogh, Thomas J Meyer, Maggie Cam, Debra Shearer, Matthew Lanza, Neil D Christensen, Zhi-Ming Zheng

{"title":"The full transcription map of cottontail rabbit papillomavirus in tumor tissues.","authors":"Pengfei Jiang, Vladimir Majerciak, Jiafen Hu, Karla Balogh, Thomas J Meyer, Maggie Cam, Debra Shearer, Matthew Lanza, Neil D Christensen, Zhi-Ming Zheng","doi":"10.1371/journal.ppat.1012649","DOIUrl":"10.1371/journal.ppat.1012649","url":null,"abstract":"Cottontail rabbit papillomavirus (CRPV), the first papillomavirus associated with tumor development, has been used as a powerful model to study papillomavirus pathogenesis for more than 90 years. However, lack of a comprehensive analysis of the CRPV transcriptome has impeded the understanding of CRPV biology and molecular pathogenesis. Here, we report the construction of a complete CRPV transcription map from Hershey CRPV-induced skin tumor tissues. By using RNA-seq in combination with long-reads PacBio Iso-seq, 5' and 3' RACE, primer-walking RT-PCR, Northern blot, and RNA in situ hybridization, we demonstrated that the CRPV genome transcribes its early and late RNA transcripts unidirectionally from at least five distinct major promoters (P) and polyadenylates its transcripts at two major polyadenylation (pA) sites. The viral early transcripts are primarily transcribed from three \"early\" promoters, P90, P156, and P907 and polyadenylated at nt 4368 by using an early polyadenylation signal (PAS) at nt 4351. Like other low-risk human papillomaviruses and animal papillomaviruses, CRPV E6 and E7 transcripts are transcribed from three separate early promoters. Transcripts from two \"late\" promoters, P7525, and P1225, utilize either an early PAS for E1^E4 or a late PAS at 7399 for L2 and L1 RNA polyadenylation at nt 7415 to express capsid L2 and L1 proteins respectively. By using the mapped four 5' splice sites and three 3' splice sites, CRPV RNA transcripts undergo extensive alternative splicing to produce more than 33 viral RNA isoforms for production of at least 12 viral proteins, some of which without codon optimization are expressible in rabbit RK13 and human HEK293T cells. The constructed full CRPV transcription map in this study for the first time will enhance our understanding of the structures and expressions of CRPV genes and their contribution to molecular pathogenesis and tumorigenesis.","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511103","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}

引用次数: 0

Caspase-1 in Cx3cr1-expressing cells drives an IL-18-dependent T cell response that promotes parasite control during acute Toxoplasma gondii infection. Cx3cr1表达细胞中的Caspase-1驱动IL-18依赖性T细胞反应，从而在弓形虫急性感染期间促进对寄生虫的控制。

IF 5.5 1区医学

PLoS Pathogens Pub Date : 2024-10-24 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012006

Isaac W Babcock, Lydia A Sibley, Sydney A Labuzan, Maureen N Cowan, Ish Sethi, Seblework Alemu, Abigail G Kelly, Michael A Kovacs, John R Lukens, Tajie H Harris

{"title":"Caspase-1 in Cx3cr1-expressing cells drives an IL-18-dependent T cell response that promotes parasite control during acute Toxoplasma gondii infection.","authors":"Isaac W Babcock, Lydia A Sibley, Sydney A Labuzan, Maureen N Cowan, Ish Sethi, Seblework Alemu, Abigail G Kelly, Michael A Kovacs, John R Lukens, Tajie H Harris","doi":"10.1371/journal.ppat.1012006","DOIUrl":"10.1371/journal.ppat.1012006","url":null,"abstract":"Inflammasome activation is a robust innate immune mechanism that promotes inflammatory responses through the release of alarmins and leaderless cytokines, including IL-1α, IL-1β, and IL-18. Various stimuli, including infectious agents and cellular stress, cause inflammasomes to assemble and activate caspase-1. Then, caspase-1 cleaves targets that lead to pore formation and leaderless cytokine activation and release. Toxoplasma gondii has been shown to promote inflammasome formation, but the cell types utilizing caspase-1 and the downstream effects on immunological outcomes during acute in vivo infection have not been explored. Here, using knockout mice, we examine the role of caspase-1 responses during acute T. gondii infection globally and in Cx3cr1-positive populations. We provide in vivo evidence that caspase-1 expression is critical for, IL-18 release, optimal interferon-γ (IFN-γ) production, monocyte and neutrophil recruitment to the site of infection, and parasite control. Specifically, we find that caspase-1 expression in Cx3cr1-positive cells drives IL-18 release, which potentiates CD4+ T cell IFN-γ production and parasite control. Notably, our Cx3cr1-Casp1 knockouts exhibited a selective T cell defect, mirroring the phenotype observed in Il18 knockouts. In further support of this finding, treatment of Cx3cr1-Casp1 knockout mice with recombinant IL-18 restored CD4+ T cell IFN-γ responses and parasite control. Additionally, we show that neutrophil recruitment is dependent on IL-1 receptor accessory protein (IL-1RAP) signaling but is dispensable for parasite control. Overall, these experiments highlight the multifaceted role of caspase-1 in multiple cell populations contributing to specific pathways that collectively contribute to caspase-1 dependent immunity to T. gondii.","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511101","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}

引用次数: 0