Pub Date : 2026-02-03eCollection Date: 2026-02-01DOI: 10.1371/journal.ppat.1013336
Ray T Y So, Kenrie P Y Hui, John C W Ho, Kaman K M Lau, Ziqi Zhou, Michael C W Chan, Leo L M Poon, Malik Peiris
Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging coronavirus that can cause zoonotic disease in humans with lethal severe viral pneumonia. Dromedary camels are the source of zoonotic infection. As of November 2025, MERS-CoV has resulted in a total of 2630 reported cases, 37% of these being fatal. The number of reported human cases has been on a decreasing trend since 2016 and reached a nadir during the COVID-19 pandemic. The reason for the reduction of cases is unclear and may be multifactorial. We hypothesized that mutations accumulating in the virus spike protein may have reduced zoonotic potential. Here, we investigate the impact of recently emerged virus spike-protein mutations on virus replication competence using pseudoviruses and replication-competent recombinant viruses. We found that virus spike variants detected in 2019 and some from 2023 show a reduced cell entry, lower viral replication and reduced fitness in human primary alveolar epithelial cells and multiple cell lines. All the MERS-CoV spikes tested showed a cell-entry pathway preference via the cell-surface TMPRSS2 route. Mechanistically, we showed the V530A mutation in the 2019 spike sequence had a reduced human DPP4 binding phenotype. Our data highlighted MERS-CoV spike mutations can modulate viral fitness in human cells and provide new insights to understand recent MERS epidemiology.
{"title":"The impact of clade B lineage 5 MERS coronaviruses spike mutations from 2015 to 2023 on virus entry and replication competence.","authors":"Ray T Y So, Kenrie P Y Hui, John C W Ho, Kaman K M Lau, Ziqi Zhou, Michael C W Chan, Leo L M Poon, Malik Peiris","doi":"10.1371/journal.ppat.1013336","DOIUrl":"10.1371/journal.ppat.1013336","url":null,"abstract":"<p><p>Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging coronavirus that can cause zoonotic disease in humans with lethal severe viral pneumonia. Dromedary camels are the source of zoonotic infection. As of November 2025, MERS-CoV has resulted in a total of 2630 reported cases, 37% of these being fatal. The number of reported human cases has been on a decreasing trend since 2016 and reached a nadir during the COVID-19 pandemic. The reason for the reduction of cases is unclear and may be multifactorial. We hypothesized that mutations accumulating in the virus spike protein may have reduced zoonotic potential. Here, we investigate the impact of recently emerged virus spike-protein mutations on virus replication competence using pseudoviruses and replication-competent recombinant viruses. We found that virus spike variants detected in 2019 and some from 2023 show a reduced cell entry, lower viral replication and reduced fitness in human primary alveolar epithelial cells and multiple cell lines. All the MERS-CoV spikes tested showed a cell-entry pathway preference via the cell-surface TMPRSS2 route. Mechanistically, we showed the V530A mutation in the 2019 spike sequence had a reduced human DPP4 binding phenotype. Our data highlighted MERS-CoV spike mutations can modulate viral fitness in human cells and provide new insights to understand recent MERS epidemiology.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 2","pages":"e1013336"},"PeriodicalIF":4.9,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12904574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146114440","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}
Epigenetic suppression and durable silencing of HIV represent a promising strategy to achieve ART-free remission, consistent with the "block and lock" HIV cure paradigm. BRD4 is a host epigenetic reader and plays a critical role in HIV transcriptional regulation. We previously identified ZL0580, a first-in-class BRD4-selective small molecule distinct from the pan-BET inhibitor JQ1, which induces HIV epigenetic suppression. However, detailed molecular mechanisms, pharmacokinetics (PK), and in vivo HIV-suppressive efficacy of ZL0580 remain undefined. Here, we show that ZL0580 selectively targets BRD4 bromodomain 1 (BD1) through interaction with a key glutamic acid residue (E151), as determined by structural modeling and mutagenesis. Transcriptomic profiling by RNA-seq reveals that ZL0580 and JQ1 induce opposing gene expression programs, consistent with their distinct effects on HIV proviral transcription and latency. In a humanized mouse model of HIV infection, ZL0580 monotherapy, or in combination with ART, potently suppressed active HIV replication, reducing the plasma viremia to nearly undetectable levels, and delayed viral rebound following treatment interruption. Collectively, these findings establish ZL0580 as an epigenetic suppressor of HIV in vivo and provide proof-of-concept for its potential as a "block and lock" HIV cure candidate, warranting further optimization and development.
{"title":"Mechanistic insights and in vivo HIV suppression by the BRD4-targeting small molecule ZL0580.","authors":"Naveen Kumar, Zonghui Ma, Fuquan Long, Srinivasa Reddy Bonam, Hsien-Tsung Lai, Shwu-Yuan Wu, Haiying Chen, Nicholas C Hazell, Jiani Bei, Xuefeng Liu, Yeqing Chen, Zhi Wei, Cheng-Ming Chiang, Jia Zhou, Haitao Hu","doi":"10.1371/journal.ppat.1013449","DOIUrl":"10.1371/journal.ppat.1013449","url":null,"abstract":"<p><p>Epigenetic suppression and durable silencing of HIV represent a promising strategy to achieve ART-free remission, consistent with the \"block and lock\" HIV cure paradigm. BRD4 is a host epigenetic reader and plays a critical role in HIV transcriptional regulation. We previously identified ZL0580, a first-in-class BRD4-selective small molecule distinct from the pan-BET inhibitor JQ1, which induces HIV epigenetic suppression. However, detailed molecular mechanisms, pharmacokinetics (PK), and in vivo HIV-suppressive efficacy of ZL0580 remain undefined. Here, we show that ZL0580 selectively targets BRD4 bromodomain 1 (BD1) through interaction with a key glutamic acid residue (E151), as determined by structural modeling and mutagenesis. Transcriptomic profiling by RNA-seq reveals that ZL0580 and JQ1 induce opposing gene expression programs, consistent with their distinct effects on HIV proviral transcription and latency. In a humanized mouse model of HIV infection, ZL0580 monotherapy, or in combination with ART, potently suppressed active HIV replication, reducing the plasma viremia to nearly undetectable levels, and delayed viral rebound following treatment interruption. Collectively, these findings establish ZL0580 as an epigenetic suppressor of HIV in vivo and provide proof-of-concept for its potential as a \"block and lock\" HIV cure candidate, warranting further optimization and development.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 2","pages":"e1013449"},"PeriodicalIF":4.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12880750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146108215","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}
Pub Date : 2026-02-02eCollection Date: 2026-02-01DOI: 10.1371/journal.ppat.1013912
Kyle Rosinke, Shoichi Tachiyama, Jan Mrázek, Jun Liu, Timothy R Hoover
[This corrects the article DOI: 10.1371/journal.ppat.1012860.].
[这更正了文章DOI: 10.1371/journal.ppat.1012860.]。
{"title":"Correction: A Helicobacter pylori flagellar motor accessory is needed to maintain the barrier function of the outer membrane during flagellar rotation.","authors":"Kyle Rosinke, Shoichi Tachiyama, Jan Mrázek, Jun Liu, Timothy R Hoover","doi":"10.1371/journal.ppat.1013912","DOIUrl":"10.1371/journal.ppat.1013912","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1371/journal.ppat.1012860.].</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 2","pages":"e1013912"},"PeriodicalIF":4.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12863469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146108143","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}
Pub Date : 2026-02-02eCollection Date: 2026-02-01DOI: 10.1371/journal.ppat.1013925
Dagmara I Kisiela, Pearl Magala, Gianluca Interlandi, Laura A Carlucci, Angelo Ramos, Veronika Tchesnokova, Benjamin Basanta, Vladimir Yarov-Yarovoy, Hovhannes Avagyan, Anahit Hovhannisyan, Wendy E Thomas, Ronald E Stenkamp, Rachel E Klevit, Evgeni V Sokurenko
[This corrects the article DOI: 10.1371/journal.ppat.1009440.].
[这更正了文章DOI: 10.1371/journal.ppat.1009440.]。
{"title":"Correction: Toggle switch residues control allosteric transitions in bacterial adhesins by participating in a concerted repacking of the protein core.","authors":"Dagmara I Kisiela, Pearl Magala, Gianluca Interlandi, Laura A Carlucci, Angelo Ramos, Veronika Tchesnokova, Benjamin Basanta, Vladimir Yarov-Yarovoy, Hovhannes Avagyan, Anahit Hovhannisyan, Wendy E Thomas, Ronald E Stenkamp, Rachel E Klevit, Evgeni V Sokurenko","doi":"10.1371/journal.ppat.1013925","DOIUrl":"10.1371/journal.ppat.1013925","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1371/journal.ppat.1009440.].</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 2","pages":"e1013925"},"PeriodicalIF":4.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12863489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146108177","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}
Pub Date : 2026-02-02eCollection Date: 2026-02-01DOI: 10.1371/journal.ppat.1013247
Andreea Mesesan, Henry Oehler, Collins Waguia Kontchou, Aladin Haimovici, Martin Helmstädter, Oliver Kretz, Oliver Schilling, Stefan Tholen, John Atanga, Irina Nazarenko, Ulf Matti, Jonas Ries, Ian E Gentle, Georg Häcker
Chlamydiae are obligate intracellular bacteria that inhibit mitochondrial apoptosis to maintain integrity of the host cell. We have previously reported that a chlamydial outer membrane β-barrel protein, OmpA, can during ectopic expression inhibit mitochondrial apoptosis through direct interaction with the BCL-2-family effectors BAX and BAK. We here show that OmpA from Chlamydia trachomatis (Ctr) uses membrane vesicles for its delivery to the outer mitochondrial membrane during Ctr infection. Using a number of imaging and fractionation techniques, we show that OmpA during infection reaches mitochondria and is inserted into mitochondrial membranes. Chlamydia derived vesicles (CDV) from Ctr-infected cells contained OmpA as well as other outer membrane proteins and LPS. When added to uninfected cells, CDVs fused with mitochondrial membranes, causing the interaction of OmpA with BAK and the cytosolic retro-translocation of BAX. CDV addition to uninfected cells also protected the cells against apoptosis. We previously showed that OmpA works in co-ordination with VDAC2 to block apoptosis and here propose a structural model of this BAK inhibition by OmpA that reenacts the inhibition of BAK by VDAC2. The results provide evidence that OmpA from Chlamydia, as well as the structurally similar ortholog from the related Simkania, specifically exploits its relationship to mitochondrial porins to protect the infected cell against apoptosis and to enable intracellular growth of the bacteria in human cells.
{"title":"Chlamydial membrane vesicles deliver the beta barrel outer membrane protein OmpA to mitochondria to inhibit apoptosis.","authors":"Andreea Mesesan, Henry Oehler, Collins Waguia Kontchou, Aladin Haimovici, Martin Helmstädter, Oliver Kretz, Oliver Schilling, Stefan Tholen, John Atanga, Irina Nazarenko, Ulf Matti, Jonas Ries, Ian E Gentle, Georg Häcker","doi":"10.1371/journal.ppat.1013247","DOIUrl":"10.1371/journal.ppat.1013247","url":null,"abstract":"<p><p>Chlamydiae are obligate intracellular bacteria that inhibit mitochondrial apoptosis to maintain integrity of the host cell. We have previously reported that a chlamydial outer membrane β-barrel protein, OmpA, can during ectopic expression inhibit mitochondrial apoptosis through direct interaction with the BCL-2-family effectors BAX and BAK. We here show that OmpA from Chlamydia trachomatis (Ctr) uses membrane vesicles for its delivery to the outer mitochondrial membrane during Ctr infection. Using a number of imaging and fractionation techniques, we show that OmpA during infection reaches mitochondria and is inserted into mitochondrial membranes. Chlamydia derived vesicles (CDV) from Ctr-infected cells contained OmpA as well as other outer membrane proteins and LPS. When added to uninfected cells, CDVs fused with mitochondrial membranes, causing the interaction of OmpA with BAK and the cytosolic retro-translocation of BAX. CDV addition to uninfected cells also protected the cells against apoptosis. We previously showed that OmpA works in co-ordination with VDAC2 to block apoptosis and here propose a structural model of this BAK inhibition by OmpA that reenacts the inhibition of BAK by VDAC2. The results provide evidence that OmpA from Chlamydia, as well as the structurally similar ortholog from the related Simkania, specifically exploits its relationship to mitochondrial porins to protect the infected cell against apoptosis and to enable intracellular growth of the bacteria in human cells.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 2","pages":"e1013247"},"PeriodicalIF":4.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12890168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146108171","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}
Porcine astrovirus (PAstV) is an important and widespread pathogen in swine, linked to diarrheal outbreaks and extraintestinal disease. How PAstV enters host cells has remained unclear, and no cellular factor has been defined for PAstV entry. Here, a genome-wide CRISPR-Cas9 loss-of-function screen in porcine epithelial cells identifies Annexin A1 (ANXA1) as a host factor that facilitates PAstV entry. Genetic ablation or pharmacological/antibody blockade of ANXA1 reduces binding, lowers early viral RNA and capsid signals, and delays the rise of progeny, whereas re-expression restores susceptibility. Biochemical assays and surface plasmon resonance indicate a direct interaction between ANXA1 and the acidic C-terminal domain of the PAstV ORF2 capsid protein, and imaging shows ANXA1 co-localizes with incoming particles at the cell surface and supports attachment and uptake. Loss of ANXA1 does not alter infection by the non-astrovirus panel tested, indicating selectivity for PAstV under our conditions. Notably, infection is reduced but not abolished in ANXA1-deficient cells, consistent with additional entry factors acting alongside ANXA1. These findings position ANXA1 as an entry cofactor for PAstV and provide a mechanistic basis to refine models of astrovirus host-cell recognition.
{"title":"Genome-wide CRISPR screening identifies Annexin A1 as a facilitator of porcine astrovirus entry.","authors":"Yuhang Luo, Qingting Dong, Shiqin Yi, Wenting Zhang, Yiyang Du, Qingli Fang, Wenchao Zhang, Kang Ouyang, Ying Chen, Yeshi Yin, Zuzhang Wei, Yifeng Qin, Weijian Huang","doi":"10.1371/journal.ppat.1013943","DOIUrl":"10.1371/journal.ppat.1013943","url":null,"abstract":"<p><p>Porcine astrovirus (PAstV) is an important and widespread pathogen in swine, linked to diarrheal outbreaks and extraintestinal disease. How PAstV enters host cells has remained unclear, and no cellular factor has been defined for PAstV entry. Here, a genome-wide CRISPR-Cas9 loss-of-function screen in porcine epithelial cells identifies Annexin A1 (ANXA1) as a host factor that facilitates PAstV entry. Genetic ablation or pharmacological/antibody blockade of ANXA1 reduces binding, lowers early viral RNA and capsid signals, and delays the rise of progeny, whereas re-expression restores susceptibility. Biochemical assays and surface plasmon resonance indicate a direct interaction between ANXA1 and the acidic C-terminal domain of the PAstV ORF2 capsid protein, and imaging shows ANXA1 co-localizes with incoming particles at the cell surface and supports attachment and uptake. Loss of ANXA1 does not alter infection by the non-astrovirus panel tested, indicating selectivity for PAstV under our conditions. Notably, infection is reduced but not abolished in ANXA1-deficient cells, consistent with additional entry factors acting alongside ANXA1. These findings position ANXA1 as an entry cofactor for PAstV and provide a mechanistic basis to refine models of astrovirus host-cell recognition.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 2","pages":"e1013943"},"PeriodicalIF":4.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12880748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146108174","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}
Pub Date : 2026-01-30eCollection Date: 2026-01-01DOI: 10.1371/journal.ppat.1013897
Yazmin B Martinez-Martinez, Matthew B Huante, Kubra F Naqvi, Mithil N Shah, Joshua G Lisinicchia, Megan A Files, Jaid Perez, Benjamin B Gelman, Mark A Endsley, Janice J Endsley
Tuberculosis (TB) kills an estimated 1.25 million people annually and is the leading cause of death in people with HIV (PWH) (1). The CD4+ T helper (Th) populations play significant roles in protective immunity to Mycobacterium tuberculosis (Mtb) and are essential hosts for HIV pathogenesis. Emerging evidence in blood and gastrointestinal mucosa of PWH suggests that, among Th cells, Th17 and Th22 may be preferentially depleted during HIV infection. Targeting of Th17 and Th22 cells by HIV could pose important and poorly understood risks for Mtb containment in those with co-infection. Mtb-driven activation of Th17 and Th22 immunity may also contribute to HIV proliferation and persistence. We employed a humanized mouse model of co-infection to assess changes in Th17 and Th22 frequency and function due to infection with HIV, Mtb, or both. In infected mice, Th17 cells were the predominant host for HIV in spleen and shown to be a source of HIV replication in pulmonary TB granulomas. Th17 cells were increased in lung of mice with TB or TB-HIV. Conversely, Th22 cells were reduced in mice with HIV or TB-HIV. Mtb infection increased the viral load in lungs of co-infected mice while HIV suppressed the pulmonary Th17 family cytokine response to Mtb including IL-6, IL-22, IL-23, and IL-1β. Differential transcriptome assessment demonstrated that HIV co-infection disrupted Th17 pathways activated by Mtb in lung. Overall, these results suggest that HIV may compromise Th22 immunity and exploit Th17 cells to promote viral pathogenesis in the setting of Mtb and HIV co-infection.
{"title":"HIV impairs and exploits pulmonary Th17 and Th22 cell-mediated immune responses to Mycobacterium tuberculosis.","authors":"Yazmin B Martinez-Martinez, Matthew B Huante, Kubra F Naqvi, Mithil N Shah, Joshua G Lisinicchia, Megan A Files, Jaid Perez, Benjamin B Gelman, Mark A Endsley, Janice J Endsley","doi":"10.1371/journal.ppat.1013897","DOIUrl":"10.1371/journal.ppat.1013897","url":null,"abstract":"<p><p>Tuberculosis (TB) kills an estimated 1.25 million people annually and is the leading cause of death in people with HIV (PWH) (1). The CD4+ T helper (Th) populations play significant roles in protective immunity to Mycobacterium tuberculosis (Mtb) and are essential hosts for HIV pathogenesis. Emerging evidence in blood and gastrointestinal mucosa of PWH suggests that, among Th cells, Th17 and Th22 may be preferentially depleted during HIV infection. Targeting of Th17 and Th22 cells by HIV could pose important and poorly understood risks for Mtb containment in those with co-infection. Mtb-driven activation of Th17 and Th22 immunity may also contribute to HIV proliferation and persistence. We employed a humanized mouse model of co-infection to assess changes in Th17 and Th22 frequency and function due to infection with HIV, Mtb, or both. In infected mice, Th17 cells were the predominant host for HIV in spleen and shown to be a source of HIV replication in pulmonary TB granulomas. Th17 cells were increased in lung of mice with TB or TB-HIV. Conversely, Th22 cells were reduced in mice with HIV or TB-HIV. Mtb infection increased the viral load in lungs of co-infected mice while HIV suppressed the pulmonary Th17 family cytokine response to Mtb including IL-6, IL-22, IL-23, and IL-1β. Differential transcriptome assessment demonstrated that HIV co-infection disrupted Th17 pathways activated by Mtb in lung. Overall, these results suggest that HIV may compromise Th22 immunity and exploit Th17 cells to promote viral pathogenesis in the setting of Mtb and HIV co-infection.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 1","pages":"e1013897"},"PeriodicalIF":4.9,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12872012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146094620","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}
Pub Date : 2026-01-30eCollection Date: 2026-01-01DOI: 10.1371/journal.ppat.1013906
Chenliang Zhou, Hong He, Yuzai Zhang, Xiaolian Liu, Muye Xia, Jiayin Qiu, Ziyao Wu, Huba Khamis Rashid, Wenli Liu, Jie Peng, Lin Li
The latency of human immunodeficiency virus type 1 (HIV-1) is a major barrier to achieving an HIV-1 cure, as antiretroviral therapy does not target the latent virus. Virus-host interactions play an essential role in various stages of the HIV-1 lifecycle. Exploring the interaction between host factors and HIV-1 infection is critical for developing new HIV-1 treatment strategies. Yes-associated protein (YAP) is a key co-transcription factor in the Hippo signaling pathway, which regulates the occurrence and development of various diseases, including cellular metabolism, cancer, immunity, and viral infection. In this study, we first confirmed that YAP gene expression in patients with acquired immune deficiency syndrome (AIDS) was significantly lower than that in the healthy control group, as determined using the GEO2R online tool. Furthermore, YAP was identified as a negative regulator of HIV-1 transcription by mediating K33- and K48-linked ubiquitination and proteasomal degradation of Tat. Here, we further confirmed that the YAP TAD domain recruited ubiquitin-like with PHD and RING finger domain 1 (UHRF1) to mediate Tat's ubiquitination and degradation by the screening of the BioGRID database combined with IP-MS analysis. The conserved lysine residues K28, K29, and K41 on Tat were critical acceptor sites for ubiquitination and proteasomal degradation. Our findings revealed that YAP promotes the suppression of HIV-1 transcription and the maintenance of HIV-1 latency, providing novel insights into virus-host interactions for regulating HIV-1 latency.
人类免疫缺陷病毒1型(HIV-1)的潜伏期是实现HIV-1治愈的主要障碍,因为抗逆转录病毒治疗并不针对潜伏病毒。病毒-宿主相互作用在HIV-1生命周期的各个阶段起着至关重要的作用。探索宿主因子与HIV-1感染之间的相互作用对于开发新的HIV-1治疗策略至关重要。Yes-associated protein (YAP)是Hippo信号通路中一个关键的共转录因子,调控多种疾病的发生发展,包括细胞代谢、癌症、免疫、病毒感染等。在这项研究中,我们首先通过GEO2R在线工具证实,获得性免疫缺陷综合征(AIDS)患者的YAP基因表达明显低于健康对照组。此外,通过介导K33和k48相关的泛素化和Tat的蛋白酶体降解,YAP被鉴定为HIV-1转录的负调节因子。本研究通过筛选BioGRID数据库并结合IP-MS分析,进一步证实了YAP TAD结构域募集泛素样PHD和RING finger domain 1 (UHRF1)介导Tat的泛素化和降解。Tat上保守的赖氨酸残基K28、K29和K41是泛素化和蛋白酶体降解的关键受体位点。我们的研究结果表明,YAP促进抑制HIV-1转录和维持HIV-1潜伏期,为病毒-宿主相互作用调节HIV-1潜伏期提供了新的见解。
{"title":"YAP Inhibits HIV-1 transcription and promotes HIV-1 latency by regulating E3 ubiquitin ligase UHRF1 mediated tat degradation.","authors":"Chenliang Zhou, Hong He, Yuzai Zhang, Xiaolian Liu, Muye Xia, Jiayin Qiu, Ziyao Wu, Huba Khamis Rashid, Wenli Liu, Jie Peng, Lin Li","doi":"10.1371/journal.ppat.1013906","DOIUrl":"10.1371/journal.ppat.1013906","url":null,"abstract":"<p><p>The latency of human immunodeficiency virus type 1 (HIV-1) is a major barrier to achieving an HIV-1 cure, as antiretroviral therapy does not target the latent virus. Virus-host interactions play an essential role in various stages of the HIV-1 lifecycle. Exploring the interaction between host factors and HIV-1 infection is critical for developing new HIV-1 treatment strategies. Yes-associated protein (YAP) is a key co-transcription factor in the Hippo signaling pathway, which regulates the occurrence and development of various diseases, including cellular metabolism, cancer, immunity, and viral infection. In this study, we first confirmed that YAP gene expression in patients with acquired immune deficiency syndrome (AIDS) was significantly lower than that in the healthy control group, as determined using the GEO2R online tool. Furthermore, YAP was identified as a negative regulator of HIV-1 transcription by mediating K33- and K48-linked ubiquitination and proteasomal degradation of Tat. Here, we further confirmed that the YAP TAD domain recruited ubiquitin-like with PHD and RING finger domain 1 (UHRF1) to mediate Tat's ubiquitination and degradation by the screening of the BioGRID database combined with IP-MS analysis. The conserved lysine residues K28, K29, and K41 on Tat were critical acceptor sites for ubiquitination and proteasomal degradation. Our findings revealed that YAP promotes the suppression of HIV-1 transcription and the maintenance of HIV-1 latency, providing novel insights into virus-host interactions for regulating HIV-1 latency.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 1","pages":"e1013906"},"PeriodicalIF":4.9,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12857974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146094693","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}
Pub Date : 2026-01-30eCollection Date: 2026-01-01DOI: 10.1371/journal.ppat.1013919
Trevor Cross, Facundo Torres, Nadia Nikulin, Abigail P McGee, Leena Jalees, Rhea Balakrishnan, Tolani Aliyu, Lars F Westblade, Abhyudai Singh, Tobias Dörr
Antibiotic tolerance is the ability of bacteria to survive normally lethal doses of antibiotics for extended time periods. Clinically significant Enterobacterales, for example, can exhibit high tolerance to the last-resort antibiotic meropenem. Meropenem tolerance is associated with formation of cell wall-deficient spheroplasts that readily recover to rod shape and normal growth upon removal of the antibiotic. Both the true prevalence of tolerance, and genetic mechanisms underlying it, remain poorly understood. Here, we find that meropenem tolerance is widespread among clinical Enterobacterales. Using forward genetics, we uncover tolerance factors in a hypertolerant isolate of the ESKAPE pathogen Klebsiella pneumoniae. We find that multiple mechanisms contribute to tolerance, and that cell envelope stress responses (PhoPQ, CpxPRA, Rcs phosphorelay and OmpR/EnvZ) collectively promote spheroplast stability and recovery, while the lytic transglycosylase MltB counteracts it. Our data indicate that tolerance is widespread among clinical isolates, and that outer membrane maintenance is a key factor promoting survival of tolerant K. pneumoniae.
{"title":"Prevalence and mechanisms of high-level carbapenem antibiotic tolerance in clinical isolates of Klebsiella pneumoniae.","authors":"Trevor Cross, Facundo Torres, Nadia Nikulin, Abigail P McGee, Leena Jalees, Rhea Balakrishnan, Tolani Aliyu, Lars F Westblade, Abhyudai Singh, Tobias Dörr","doi":"10.1371/journal.ppat.1013919","DOIUrl":"10.1371/journal.ppat.1013919","url":null,"abstract":"<p><p>Antibiotic tolerance is the ability of bacteria to survive normally lethal doses of antibiotics for extended time periods. Clinically significant Enterobacterales, for example, can exhibit high tolerance to the last-resort antibiotic meropenem. Meropenem tolerance is associated with formation of cell wall-deficient spheroplasts that readily recover to rod shape and normal growth upon removal of the antibiotic. Both the true prevalence of tolerance, and genetic mechanisms underlying it, remain poorly understood. Here, we find that meropenem tolerance is widespread among clinical Enterobacterales. Using forward genetics, we uncover tolerance factors in a hypertolerant isolate of the ESKAPE pathogen Klebsiella pneumoniae. We find that multiple mechanisms contribute to tolerance, and that cell envelope stress responses (PhoPQ, CpxPRA, Rcs phosphorelay and OmpR/EnvZ) collectively promote spheroplast stability and recovery, while the lytic transglycosylase MltB counteracts it. Our data indicate that tolerance is widespread among clinical isolates, and that outer membrane maintenance is a key factor promoting survival of tolerant K. pneumoniae.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 1","pages":"e1013919"},"PeriodicalIF":4.9,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12880740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146094710","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}
Pub Date : 2026-01-30eCollection Date: 2026-01-01DOI: 10.1371/journal.ppat.1013918
Júlia de Fraga Sant'Ana, Lucélia Santi, Walter Orlando Beys-da-Silva
{"title":"Metarhizium anisopliae: A fungal biocontrol agent against Rhipicephalus microplus.","authors":"Júlia de Fraga Sant'Ana, Lucélia Santi, Walter Orlando Beys-da-Silva","doi":"10.1371/journal.ppat.1013918","DOIUrl":"10.1371/journal.ppat.1013918","url":null,"abstract":"","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"22 1","pages":"e1013918"},"PeriodicalIF":4.9,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12857945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146094737","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}