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Antigen flexibility supports the avidity of hemagglutinin-specific antibodies at low antigen densities. 抗原的灵活性支持在低抗原密度的血凝素特异性抗体的贪婪。
IF 4.9 1区 医学 Q1 MICROBIOLOGY Pub Date : 2026-02-05 DOI: 10.1371/journal.ppat.1013862
Ananya Benegal, Yuanyuan He, Katilyn Ho, Giselle Groff, Zijian Guo, Michael D Vahey

The receptor-binding protein of influenza A virus, hemagglutinin (HA), is the most abundant protein on the viral surface. While high densities of HA are thought to improve cellular attachment by increasing avidity for the viral receptor, they may also increase the avidity of neutralizing antibodies. The tradeoff between these two competing effects of avidity is not well understood. To better understand how features of the viral surface influence antibody avidity, we developed fluorescence-based assays to measure dissociation kinetics and steady-state binding of antibodies to intact virions. Focusing on two antibodies that bind to the HA head domain (S139/1 and C05), we confirm that binding orientations that favor bivalent attachment of antibodies to the viral surface can offset weak monovalent affinity by facilitating crosslinking. By modulating HA density in both engineered viruses and synthetic nanoparticles, we find that bivalent antibody binding remains resilient down to one-tenth the HA density on the viral surface and, in the case of C05, that antibody occupancy increases at these lowest densities. Finally, using a combination of structure-guided modeling and antibodies that lock HA in a tilted conformation, we identify flexibility of the HA ectodomain as an additional determinant of antibody avidity. Together, these results establish features of the viral surface that help support or suppress the binding of neutralizing antibodies.

甲型流感病毒的受体结合蛋白血凝素(HA)是病毒表面最丰富的蛋白。虽然高密度的透明质酸被认为通过增加对病毒受体的亲和力来改善细胞附着,但它们也可能增加中和抗体的亲和力。贪婪的这两种相互竞争的影响之间的权衡还没有得到很好的理解。为了更好地了解病毒表面的特征如何影响抗体的亲和力,我们开发了基于荧光的检测方法来测量抗体与完整病毒粒子的解离动力学和稳态结合。重点研究了两种结合HA头部结构域的抗体(S139/1和C05),我们证实了有利于抗体与病毒表面二价附着的结合方向可以通过促进交联来抵消弱的单价亲和力。通过调节工程病毒和合成纳米颗粒中的透明质酸密度,我们发现二价抗体结合保持弹性,低至病毒表面透明质酸密度的十分之一,并且在C05的情况下,抗体占用率在这些最低密度下增加。最后,结合结构引导建模和将HA锁定在倾斜构象的抗体,我们确定了HA外结构域的灵活性是抗体亲和力的另一个决定因素。总之,这些结果确定了病毒表面有助于支持或抑制中和抗体结合的特征。
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引用次数: 0
A novel SO2 probe inhibits lysophagy induced by Senecavirus A infection by promoting LAMP1 Cys375 sulfenylation. 一种新的SO2探针通过促进LAMP1 Cys375磺化抑制塞尼卡病毒A感染诱导的溶血吞噬。
IF 4.9 1区 医学 Q1 MICROBIOLOGY Pub Date : 2026-02-05 eCollection Date: 2026-02-01 DOI: 10.1371/journal.ppat.1013932
Shuo Wang, WenWen Han, BaoXiang Zhao, Ye Hong, Jun Li, JunYing Miao, ZhaoMin Lin

Lysophagy plays a key role in maintaining autophagy homeostasis, but the induction and regulation mechanisms of lysophagy are not clear. In this study, we found that Senecavirus A (SVA) dramatically decreased lysosomal-associated membrane protein 1(LAMP1), significantly increased lysosomal permeability, and induced lysophagy. We demonstrated that the SO2 probe (2-(4-(dimethylamino-) phenyl)1,1, 3-trimethyl-1h-benzo [e] indole-3-ium, DLC) could inhibited the degradation of LAMP1 and reduced lysophagy caused by SVA infection. DLC directly binds to LAMP1, and enhanced sulfenylation modification of LAMP1 at Cys375 to inhibit non-lysine ubiquitination. Finally, we verified the antiviral effects of DLC in cells and in BALB/c mice. Taken together, our study lays the foundation for the identification of SVA infection targets and the development of antiviral drugs in the future.

自噬在维持自噬稳态中起着关键作用,但其诱导和调控机制尚不清楚。在本研究中,我们发现塞内卡病毒A (SVA)显著降低溶酶体相关膜蛋白1(LAMP1),显著增加溶酶体通透性,诱导溶噬。我们证明了SO2探针(2-(4-(二甲氨基-)苯基)1,1,3 -三甲基-1h-苯并[e]吲哚-3-ium, DLC)可以抑制LAMP1的降解并减少SVA感染引起的溶血吞噬。DLC直接结合LAMP1,增强LAMP1在Cys375上的亚砜化修饰,抑制非赖氨酸泛素化。最后,我们在细胞和BALB/c小鼠中验证了DLC的抗病毒作用。综上所述,本研究为今后SVA感染靶点的鉴定和抗病毒药物的开发奠定了基础。
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引用次数: 0
The diverse roles of host membranes in plant-microbe interactions. 寄主膜在植物与微生物相互作用中的不同作用。
IF 4.9 1区 医学 Q1 MICROBIOLOGY Pub Date : 2026-02-05 eCollection Date: 2026-02-01 DOI: 10.1371/journal.ppat.1013921
Marie-Dominique Jolivet, Hua Wei, Isabella Gantner, Andreas Klingl, Caroline Gutjahr, Julien Gronnier
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引用次数: 0
Shaping immunity: Genetic diversity as a key resource for crop protection. 塑造免疫力:遗传多样性是作物保护的关键资源。
IF 4.9 1区 医学 Q1 MICROBIOLOGY Pub Date : 2026-02-05 eCollection Date: 2026-02-01 DOI: 10.1371/journal.ppat.1013892
Amit Fenn, Samara Mireza Correia de Lemos, Thomas Lahaye, Claude Becker, Ralph Hückelhoven, Nadia Kamal
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引用次数: 0
Inhibitory NK receptor expression associates with altered antimalarial function of γδ T cells. 抑制性NK受体表达与γδ T细胞抗疟功能改变相关。
IF 4.9 1区 医学 Q1 MICROBIOLOGY Pub Date : 2026-02-03 eCollection Date: 2026-02-01 DOI: 10.1371/journal.ppat.1013460
Meagan E Olive, Perri C Callaway, Mikias Ilala, Justine Levan, Gonzalo R Acevedo, Felistas Nankya, Emmanuel Arinaitwe, John Rek, Prasanna Jagannathan, Grant Dorsey, Moses R Kamya, Margaret E Feeney

Gamma delta (γδ) T cells are important mediators of the immune response to childhood malaria. Human Vγ9+Vδ2+ T cells possess intrinsic, HLA-independent responsiveness to Plasmodium falciparum phosphoantigens produced in the blood stage of malaria. Engagement of the γδ T cell receptor (TCR) by phosphoantigen-bound butyrophilin molecules results in Vγ9+Vδ2+ T cell expansion, pro-inflammatory cytokine production, and release of cytotoxic granules that mediate parasite killing. Repeated P. falciparum infection, however, leads to a reduction in circulating Vγ9+Vδ2+ T cells and upregulation of immunomodulatory molecules, including NK receptors, that correlates with less severe symptoms upon infection. We explore phenotypic and functional differences of γδ T cells in Ugandan children with high versus low malaria exposure, utilizing high-parameter spectral flow cytometry analysis of PBMCs. We observed significant differences in expression of inhibitory NK receptors - KIR2DL1, KIR2DL2/3, KIR3DL1, LILRB1, and NKG2A - on γδ T cell subsets, with Vγ9+Vδ2+ T cells exhibiting a divergent mechanism of control compared to other subsets. We found that NKG2A and KIR3DL1 expression associated with potent Vγ9+Vδ2+ T cell responses to TCR- and Fc receptor (FcR)-mediated stimulation while KIR2DL1, KIR2DL2/3 and LILRB1 associated with reduced degranulation and cytokine production. These results identify a new role for inhibitory NK receptors expressed on γδ T cells, exerting a finely tuned balance of activating and inhibitory signals to regulate the response to malaria-related antigens.

γδ (γδ) T细胞是儿童疟疾免疫应答的重要介质。人Vγ9+Vδ2+ T细胞对疟疾血液期产生的恶性疟原虫磷酸抗原具有内在的、不依赖hla的应答性。磷酸化抗原结合的亲丁酸蛋白分子与γδ T细胞受体(TCR)结合,导致v - γ - 9+ v - δ2+ T细胞扩增、促炎细胞因子的产生和细胞毒性颗粒的释放,介导寄生虫的杀伤。然而,恶性疟原虫的反复感染导致循环中的Vγ9+Vδ2+ T细胞减少,免疫调节分子(包括NK受体)上调,这与感染后较轻的症状相关。我们利用高参数光谱流式细胞术分析pmcs,探讨了高和低疟疾暴露的乌干达儿童γδ T细胞的表型和功能差异。我们观察到抑制性NK受体KIR2DL1、KIR2DL2/3、KIR3DL1、LILRB1和NKG2A -在γδ T细胞亚群上的表达存在显著差异,与其他亚群相比,Vγ9+Vδ2+ T细胞表现出不同的控制机制。我们发现NKG2A和KIR3DL1的表达与TCR-和Fc受体(FcR)介导的刺激下v - γ - 9+ v - δ2+ T细胞的强效应答有关,而KIR2DL1、KIR2DL2/3和LILRB1与脱颗粒和细胞因子的产生减少有关。这些结果确定了在γδ T细胞上表达的抑制性NK受体的新作用,通过激活和抑制信号的精细平衡来调节对疟疾相关抗原的反应。
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引用次数: 0
The impact of clade B lineage 5 MERS coronaviruses spike mutations from 2015 to 2023 on virus entry and replication competence. 2015 - 2023年B支5型MERS冠状病毒刺突突变对病毒进入和复制能力的影响
IF 4.9 1区 医学 Q1 MICROBIOLOGY Pub Date : 2026-02-03 eCollection Date: 2026-02-01 DOI: 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.

中东呼吸综合征冠状病毒(MERS-CoV)是一种新出现的冠状病毒,可导致患有致命严重病毒性肺炎的人患人畜共患疾病。单峰骆驼是人畜共患病的传染源。截至2025年11月,中东呼吸综合征冠状病毒共报告了2630例病例,其中37%是致命的。自2016年以来,报告的人间病例数一直呈下降趋势,并在2019冠状病毒病大流行期间达到最低点。病例减少的原因尚不清楚,可能是多因素的。我们假设病毒刺突蛋白中积累的突变可能降低了人畜共患的可能性。在这里,我们利用假病毒和具有复制能力的重组病毒研究了最近出现的病毒刺突蛋白突变对病毒复制能力的影响。我们发现,2019年和2023年检测到的一些病毒刺突变异在人类原代肺泡上皮细胞和多个细胞系中显示出细胞进入减少、病毒复制减少和适应性降低。所有测试的MERS-CoV刺突均表现出通过细胞表面TMPRSS2途径进入细胞的偏好。从机制上看,我们发现2019穗序列中的V530A突变具有减少的人类DPP4结合表型。我们的数据强调了MERS- cov刺突突变可以调节人类细胞中的病毒适应性,并为了解最近的MERS流行病学提供了新的见解。
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引用次数: 0
Mechanistic insights and in vivo HIV suppression by the BRD4-targeting small molecule ZL0580. brd4靶向小分子ZL0580的机制和体内HIV抑制。
IF 4.9 1区 医学 Q1 MICROBIOLOGY Pub Date : 2026-02-02 eCollection Date: 2026-02-01 DOI: 10.1371/journal.ppat.1013449
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

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.

表观遗传抑制和HIV的持久沉默代表了实现无art缓解的有希望的策略,与“阻断和锁定”HIV治愈范例一致。BRD4是一种宿主表观遗传读本,在HIV转录调控中起关键作用。我们之前发现了ZL0580,这是一种与泛- bet抑制剂JQ1不同的同类首创的brd4选择性小分子,可诱导HIV表观遗传抑制。然而,ZL0580的详细分子机制、药代动力学(PK)和体内hiv抑制效果仍未明确。在这里,我们发现ZL0580通过与关键谷氨酸残基(E151)的相互作用选择性靶向BRD4 bromodomain 1 (BD1),这是通过结构建模和诱变确定的。RNA-seq转录组学分析显示,ZL0580和JQ1诱导相反的基因表达程序,这与它们对HIV前病毒转录和潜伏期的独特影响一致。在HIV感染人源化小鼠模型中,ZL0580单药治疗或与ART联合治疗可有效抑制活跃的HIV复制,将血浆病毒血症降低到几乎无法检测到的水平,并延迟治疗中断后的病毒反弹。总的来说,这些发现证实了ZL0580在体内是一种HIV的表观遗传抑制因子,并为其作为一种“阻断和锁定”HIV治疗候选药物的潜力提供了概念证明,值得进一步优化和开发。
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引用次数: 0
Correction: A Helicobacter pylori flagellar motor accessory is needed to maintain the barrier function of the outer membrane during flagellar rotation. 纠正:需要幽门螺杆菌鞭毛运动附件来维持鞭毛旋转时外膜的屏障功能。
IF 4.9 1区 医学 Q1 MICROBIOLOGY Pub Date : 2026-02-02 eCollection Date: 2026-02-01 DOI: 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.]。
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引用次数: 0
Chlamydial membrane vesicles deliver the beta barrel outer membrane protein OmpA to mitochondria to inhibit apoptosis. 衣原体膜囊将β桶外膜蛋白OmpA传递至线粒体,抑制细胞凋亡。
IF 4.9 1区 医学 Q1 MICROBIOLOGY Pub Date : 2026-02-02 eCollection Date: 2026-02-01 DOI: 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.

衣原体是专性细胞内细菌,抑制线粒体凋亡以维持宿主细胞的完整性。我们之前报道过衣原体外膜β-桶蛋白OmpA在异位表达时可以通过与bcl -2家族效应物BAX和BAK的直接相互作用抑制线粒体凋亡。我们在这里表明,来自沙眼衣原体(Ctr)的OmpA在Ctr感染期间使用膜泡将其传递到线粒体外膜。利用多种成像和分离技术,我们发现OmpA在感染过程中到达线粒体并插入线粒体膜。衣原体衍生囊泡(CDV)含有OmpA以及其他外膜蛋白和LPS。当加入到未感染的细胞中时,cdv与线粒体膜融合,引起OmpA与BAK的相互作用和BAX的细胞质逆行易位。CDV加入到未感染的细胞中也能保护细胞免于凋亡。我们之前的研究表明,OmpA与VDAC2协同作用以阻止细胞凋亡,并在此提出了OmpA抑制BAK的结构模型,该模型再现了VDAC2对BAK的抑制。结果表明,来自衣原体的OmpA,以及来自相关Simkania的结构相似的同源物,专门利用其与线粒体孔蛋白的关系来保护受感染的细胞免受凋亡,并使细菌在人类细胞内生长。
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引用次数: 0
Correction: Toggle switch residues control allosteric transitions in bacterial adhesins by participating in a concerted repacking of the protein core. 更正:通过参与蛋白质核心的协调重新包装,开关残基控制细菌粘附素的变构转变。
IF 4.9 1区 医学 Q1 MICROBIOLOGY Pub Date : 2026-02-02 eCollection Date: 2026-02-01 DOI: 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.]。
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引用次数: 0
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