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Protein arginine methyltransferase 6 mediates antiviral immunity in plants 精氨酸甲基转移酶 6 在植物抗病毒免疫中起介导作用
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-08-05 DOI: 10.1016/j.chom.2024.07.014

Viral suppressor RNA silencing (VSR) is essential for successful infection. Nucleotide-binding and leucine-rich repeat (NLR)-based and autophagy-mediated immune responses have been reported to target VSR as counter-defense strategies. Here, we report a protein arginine methyltransferase 6 (PRMT6)-mediated defense mechanism targeting VSR. The knockout and overexpression of PRMT6 in tomato plants lead to enhanced and reduced disease symptoms, respectively, during tomato bush stunt virus (TBSV) infection. PRMT6 interacts with and inhibits the VSR function of TBSV P19 by methylating its key arginine residues R43 and R115, thereby reducing its dimerization and small RNA-binding activities. Analysis of the natural tomato population reveals that two major alleles associated with high and low levels of PRMT6 expression are significantly associated with high and low levels of viral resistance, respectively. Our study establishes PRMT6-mediated arginine methylation of VSR as a mechanism of plant immunity against viruses.

病毒抑制RNA沉默(VSR)对成功感染至关重要。据报道,基于核苷酸结合和富亮氨酸重复序列(NLR)以及自噬介导的免疫反应可将 VSR 作为反防御策略的目标。在这里,我们报告了一种由精氨酸甲基转移酶6(PRMT6)介导的针对VSR的防御机制。在番茄灌木枯萎病病毒(TBSV)感染过程中,PRMT6 在番茄植株中的敲除和过表达分别导致病害症状的增强和减轻。PRMT6 通过甲基化 TBSV P19 的关键精氨酸残基 R43 和 R115,与 TBSV P19 相互作用并抑制其 VSR 功能,从而降低其二聚化和小 RNA 结合活性。对天然番茄种群的分析表明,与 PRMT6 高水平和低水平表达相关的两个主要等位基因分别与高水平和低水平的病毒抗性显著相关。我们的研究确定了 PRMT6 介导的 VSR 精氨酸甲基化是植物抗病毒免疫的一种机制。
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引用次数: 0
Bacterial homologs of innate eukaryotic antiviral defenses with anti-phage activity highlight shared evolutionary roots of viral defenses 具有抗噬菌体活性的先天真核生物抗病毒防御系统的细菌同源物凸显了病毒防御系统的共同进化根源
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-08-01 DOI: 10.1016/j.chom.2024.07.007

Prokaryotes have evolved a multitude of defense systems to protect against phage predation. Some of these resemble eukaryotic genes involved in antiviral responses. Here, we set out to systematically project the current knowledge of eukaryotic-like antiviral defense systems onto prokaryotic genomes, using Pseudomonas aeruginosa as a model organism. Searching for phage defense systems related to innate antiviral genes from vertebrates and plants, we uncovered over 450 candidates. We validated six of these phage defense systems, including factors preventing viral attachment, R-loop-acting enzymes, the inflammasome, ubiquitin pathway, and pathogen recognition signaling. Collectively, these defense systems support the concept of deep evolutionary links and shared antiviral mechanisms between prokaryotes and eukaryotes.

原核生物已经进化出多种防御系统来抵御噬菌体的捕食。其中一些与参与抗病毒反应的真核基因相似。在这里,我们以铜绿假单胞菌为模式生物,系统地将目前对真核生物类抗病毒防御系统的了解投射到原核生物基因组上。通过搜索脊椎动物和植物中与先天性抗病毒基因相关的噬菌体防御系统,我们发现了 450 多个候选基因。我们验证了其中六个噬菌体防御系统,包括防止病毒附着的因子、R环作用酶、炎性体、泛素途径和病原体识别信号。这些防御系统共同支持了原核生物与真核生物之间深层进化联系和共享抗病毒机制的概念。
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引用次数: 0
Viral hijacking of hnRNPH1 unveils a G-quadruplex-driven mechanism of stress control 病毒对 hnRNPH1 的劫持揭示了一种由 G 型四联体驱动的应激控制机制
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-08-01 DOI: 10.1016/j.chom.2024.07.006

Viral genomes are enriched with G-quadruplexes (G4s), non-canonical structures formed in DNA or RNA upon assembly of four guanine stretches into stacked quartets. Because of their critical roles, G4s are potential antiviral targets, yet their function remains largely unknown. Here, we characterize the formation and functions of a conserved G4 within the polymerase coding region of orthoflaviviruses of the Flaviviridae family. Using yellow fever virus, we determine that this G4 promotes viral replication and suppresses host stress responses via interactions with hnRNPH1, a host nuclear protein involved in RNA processing. G4 binding to hnRNPH1 causes its cytoplasmic retention with subsequent impacts on G4-containing tRNA fragments (tiRNAs) involved in stress-mediated reductions in translation. As a result, these host stress responses and associated antiviral effects are impaired. These data reveal that the interplay between hnRNPH1 and both host and viral G4 targets controls the integrated stress response and viral replication.

病毒基因组中富含 G-四联体(G4s),这是 DNA 或 RNA 中四个鸟嘌呤链段组装成叠加四联体后形成的非经典结构。由于其关键作用,G4s 是潜在的抗病毒靶标,但其功能在很大程度上仍不为人所知。在这里,我们描述了黄热病病毒科正黄热病病毒聚合酶编码区中保守的 G4 的形成和功能。利用黄热病病毒,我们确定这种 G4 通过与参与 RNA 处理的宿主核蛋白 hnRNPH1 相互作用,促进病毒复制并抑制宿主的应激反应。G4 与 hnRNPH1 结合会导致其在细胞质中滞留,进而影响含 G4 的 tRNA 片段(tiRNA),这些片段参与了应激介导的翻译减少。因此,这些宿主应激反应和相关的抗病毒效应受到了损害。这些数据揭示了 hnRNPH1 与宿主和病毒 G4 靶点之间的相互作用控制着综合应激反应和病毒复制。
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引用次数: 0
The bacterial defense system MADS interacts with CRISPR-Cas to limit phage infection and escape 细菌防御系统 MADS 与 CRISPR-Cas 相互作用,限制噬菌体感染和逃逸
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-08-01 DOI: 10.1016/j.chom.2024.07.005

The constant arms race between bacteria and their parasites has resulted in a large diversity of bacterial defenses, with many bacteria carrying multiple systems. Here, we report the discovery of a phylogenetically widespread defense system, coined methylation-associated defense system (MADS), which is distributed across gram-positive and gram-negative bacteria. MADS interacts with a CRISPR-Cas system in its native host to provide robust and durable resistance against phages. While phages can acquire epigenetic-mediated resistance against MADS, co-existence of MADS and a CRISPR-Cas system limits escape emergence. MADS comprises eight genes with predicted nuclease, ATPase, kinase, and methyltransferase domains, most of which are essential for either self/non-self discrimination, DNA restriction, or both. The complex genetic architecture of MADS and MADS-like systems, relative to other prokaryotic defenses, points toward highly elaborate mechanisms of sensing infections, defense activation, and/or interference.

细菌与寄生虫之间的持续军备竞赛导致细菌防御系统的多样性,许多细菌携带多种防御系统。在这里,我们报告发现了一种在系统发育上广泛存在的防御系统,被称为甲基化相关防御系统(MADS),它分布于革兰氏阳性和革兰氏阴性细菌中。MADS 与原生宿主的 CRISPR-Cas 系统相互作用,对噬菌体产生强大而持久的抵抗力。虽然噬菌体可以获得由表观遗传介导的对 MADS 的抗性,但 MADS 和 CRISPR-Cas 系统的共存限制了逃逸的出现。MADS 由 8 个基因组成,具有预测的核酸酶、ATP 酶、激酶和甲基转移酶结构域,其中大多数基因对于自我/非自我分辨、DNA 限制或两者都至关重要。与其他原核生物防御系统相比,MADS 和类似 MADS 系统的复杂基因结构表明,它们具有高度复杂的感知感染、激活防御和/或干扰的机制。
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引用次数: 0
A human commensal-pathogenic fungus suppresses host immunity via targeting TBK1 一种人类共生致病真菌通过靶向 TBK1 抑制宿主免疫力
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-07-30 DOI: 10.1016/j.chom.2024.07.003

Candida albicans stably colonizes humans but is the leading cause of hospital-acquired fungemia. Traditionally, masking immunogenic moieties has been viewed as a tactic for immune evasion. Here, we demonstrate that C. albicans blocks type I interferon (IFN-I) signaling via translocating an effector protein Cmi1 into host cells. Mechanistically, Cmi1 binds and inhibits TANK-binding kinase 1 (TBK1) to abrogate IFN-regulatory factor 3 (IRF3) phosphorylation, thereby suppressing the IFN-I cascade. Murine infection with a cmi1 mutant displays an exaggerated IFN-I response in both kidneys and bone-marrow-derived macrophages, leading to rapid fungal clearance and host survival. Remarkably, the lack of CMI1 compromises gut commensalism and increases IFN-I response in mouse colonic cells. These phenotypes of cmi1 are rescued by the depletion of IFN-I receptor. This work establishes the importance of TBK1 inhibition in fungal pathogenesis and reveals that a human commensal-pathogenic fungus significantly impacts host immunity during gut colonization and infection via delivering effector proteins into host cells.

白色念珠菌在人体内稳定定植,但却是医院获得性真菌病的主要病因。传统上,掩盖免疫原性分子被视为一种免疫逃避策略。在这里,我们证明白僵菌通过将效应蛋白 Cmi1 转运到宿主细胞中来阻断 I 型干扰素(IFN-I)信号传导。从机理上讲,Cmi1能结合并抑制TANK结合激酶1(TBK1),从而抑制IFN调节因子3(IRF3)的磷酸化,从而抑制IFN-I级联反应。小鼠感染 cmi1 突变体后,肾脏和骨髓衍生巨噬细胞中的 IFN-I 反应都会加剧,从而导致真菌快速清除和宿主存活。值得注意的是,缺乏 CMI1 会影响肠道共生,并增加小鼠结肠细胞中的 IFN-I 反应。IFN-I 受体的缺失可挽救 cmi1 的这些表型。这项研究确定了 TBK1 抑制在真菌致病过程中的重要性,并揭示了一种人类共生致病真菌在肠道定植和感染过程中通过向宿主细胞输送效应蛋白对宿主免疫产生了重大影响。
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引用次数: 0
Fecal microbiota transplantation improves anti-PD-1 inhibitor efficacy in unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor 粪便微生物群移植可提高抗PD-1抑制剂难治性不可切除或转移性实体癌的疗效
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-07-25 DOI: 10.1016/j.chom.2024.06.010

The gut microbiome significantly influences immune responses and the efficacy of immune checkpoint inhibitors. We conducted a clinical trial (NCT04264975) combining an anti-programmed death-1 (PD-1) inhibitor with fecal microbiota transplantation (FMT) from anti-PD-1 responder in 13 patients with anti-PD-1-refractory advanced solid cancers. FMT induced sustained microbiota changes and clinical benefits in 6 of 13 patients, with 1 partial response and 5 stable diseases, achieving an objective response rate of 7.7% and a disease control rate of 46.2%. The clinical response correlates with increased cytotoxic T cells and immune cytokines in blood and tumors. We isolated Prevotella merdae Immunoactis from a responder to FMT, which stimulates T cell activity and suppresses tumor growth in mice by enhancing cytotoxic T cell infiltration. Additionally, we found Lactobacillus salivarius and Bacteroides plebeius may inhibit anti-tumor immunity. Our findings suggest that FMT with beneficial microbiota can overcome resistance to anti-PD-1 inhibitors in advanced solid cancers, especially gastrointestinal cancers.

肠道微生物群对免疫反应和免疫检查点抑制剂的疗效有重大影响。我们开展了一项临床试验(NCT04264975),将抗程序性死亡-1(PD-1)抑制剂与来自抗PD-1应答者的粪便微生物群移植(FMT)相结合,治疗13例抗PD-1难治性晚期实体瘤患者。在13名患者中,有6名患者通过粪便微生物群移植获得了持续的微生物群变化和临床获益,其中1名患者部分应答,5名患者病情稳定,客观应答率达到7.7%,疾病控制率达到46.2%。临床反应与血液和肿瘤中细胞毒性 T 细胞和免疫细胞因子的增加有关。我们从一名 FMT 反应者体内分离出了 Prevotella merdae Immunoactis,它通过增强细胞毒性 T 细胞浸润来刺激 T 细胞活性并抑制小鼠体内的肿瘤生长。此外,我们还发现唾液乳杆菌(Lactobacillus salivarius)和褶状乳杆菌(Bacteroides plebeius)可能会抑制抗肿瘤免疫。我们的研究结果表明,在晚期实体瘤,尤其是胃肠道癌症中,使用有益微生物群进行FMT治疗可以克服抗PD-1抑制剂的耐药性。
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引用次数: 0
Peptostreptococcus stomatis promotes colonic tumorigenesis and receptor tyrosine kinase inhibitor resistance by activating ERBB2-MAPK 口腔普氏链球菌通过激活ERBB2-MAPK促进结肠肿瘤发生和受体酪氨酸激酶抑制剂的抗药性
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-07-25 DOI: 10.1016/j.chom.2024.07.001

Peptostreptococcus stomatis (P. stomatis) is enriched in colorectal cancer (CRC), but its causality and translational implications in CRC are unknown. Here, we show that P. stomatis accelerates colonic tumorigenesis in ApcMin/+ and azoxymethane/dextran sodium sulfate (AOM-DSS) models by inducing cell proliferation, suppressing apoptosis, and impairing gut barrier function. P. stomatis adheres to CRC cells through its surface protein fructose-1,6-bisphosphate aldolase (FBA) that binds to the integrin α6/β4 receptor on CRC cells, leading to the activation of ERBB2 and the downstream MEK-ERK-p90 cascade. Blockade of the FBA-integrin α6/β4 abolishes ERBB2-mitogen-activated protein kinase (MAPK) activation and the protumorigenic effect of P. stomatis. P. stomatis-driven ERBB2 activation bypasses receptor tyrosine kinase (RTK) blockade by EGFR inhibitors (cetuximab, erlotinib), leading to drug resistance in xenograft and spontaneous CRC models of KRAS-wild-type CRC. P. stomatis also abrogates BRAF inhibitor (vemurafenib) efficacy in BRAFV600E-mutant CRC xenografts. Thus, we identify P. stomatis as an oncogenic bacterium and a contributory factor for non-responsiveness to RTK inhibitors in CRC.

口腔普氏链球菌(P. stomatis)在结直肠癌(CRC)中富集,但其在 CRC 中的因果关系和转化意义尚不清楚。在这里,我们发现 P. stomatis 通过诱导细胞增殖、抑制细胞凋亡和损害肠道屏障功能,在 ApcMin/+ 和偶氮甲烷/葡聚糖硫酸钠(AOM-DSS)模型中加速结肠肿瘤发生。P.stomatis通过其表面蛋白果糖-1,6-二磷酸醛缩酶(FBA)粘附于CRC细胞,FBA与CRC细胞上的整合素α6/β4受体结合,导致ERBB2和下游的MEK-ERK-p90级联活化。阻断FBA-整合素α6/β4可消除ERBB2-中性粒细胞活化蛋白激酶(MAPK)的活化和P. stomatis的促瘤效应。P.stomatis驱动的ERBB2活化可绕过表皮生长因子受体抑制剂(西妥昔单抗、厄洛替尼)对受体酪氨酸激酶(RTK)的阻断,从而导致KRAS-wild型CRC异种移植和自发CRC模型产生耐药性。在 BRAFV600E 突变的 CRC 异种移植物中,P. stomatis 也会削弱 BRAF 抑制剂(vemurafenib)的疗效。因此,我们发现口疮桿菌是一种致癌细菌,也是导致 CRC 对 RTK 抑制剂无效的一个因素。
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引用次数: 0
A small intestinal bile acid modulates the gut microbiome to improve host metabolic phenotypes following bariatric surgery 一种小肠胆汁酸能调节肠道微生物组,改善减肥手术后宿主的代谢表型
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-07-22 DOI: 10.1016/j.chom.2024.06.014

Bariatric surgical procedures such as sleeve gastrectomy (SG) provide effective type 2 diabetes (T2D) remission in human patients. Previous work demonstrated that gastrointestinal levels of the bacterial metabolite lithocholic acid (LCA) are decreased after SG in mice and humans. Here, we show that LCA worsens glucose tolerance and impairs whole-body metabolism. We also show that taurodeoxycholic acid (TDCA), which is the only bile acid whose concentration increases in the murine small intestine post-SG, suppresses the bacterial bile acid-inducible (bai) operon and production of LCA both in vitro and in vivo. Treatment of diet-induced obese mice with TDCA reduces LCA levels and leads to microbiome-dependent improvements in glucose handling. Moreover, TDCA abundance is decreased in small intestinal tissue from T2D patients. This work reveals that TDCA is an endogenous inhibitor of LCA production and suggests that TDCA may contribute to the glucoregulatory effects of bariatric surgery.

袖带胃切除术(SG)等减肥手术能有效缓解人类患者的 2 型糖尿病(T2D)病情。以前的研究表明,小鼠和人类接受袖带胃切除术后,胃肠道中细菌代谢产物石胆酸(LCA)的水平会下降。在这里,我们发现 LCA 会恶化葡萄糖耐量并损害全身代谢。我们还发现,牛磺脱氧胆酸(TDCA)是小鼠小肠中唯一一种在 SG 后浓度增加的胆汁酸,它在体外和体内都能抑制细菌胆汁酸诱导(bai)操作子和 LCA 的产生。用 TDCA 治疗饮食诱导的肥胖小鼠可降低 LCA 水平,并导致葡萄糖处理的微生物依赖性改善。此外,在 T2D 患者的小肠组织中,TDCA 的丰度也有所下降。这项研究揭示了 TDCA 是 LCA 生成的内源性抑制剂,并表明 TDCA 可能有助于减肥手术的血糖调节效果。
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引用次数: 0
Age-dependent heterogeneity in the antigenic effects of mutations to influenza hemagglutinin 流感血凝素突变的抗原效应随年龄变化的异质性
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-07-19 DOI: 10.1016/j.chom.2024.06.015

Human influenza virus evolves to escape neutralization by polyclonal antibodies. However, we have a limited understanding of how the antigenic effects of viral mutations vary across the human population and how this heterogeneity affects virus evolution. Here, we use deep mutational scanning to map how mutations to the hemagglutinin (HA) proteins of two H3N2 strains, A/Hong Kong/45/2019 and A/Perth/16/2009, affect neutralization by serum from individuals of a variety of ages. The effects of HA mutations on serum neutralization differ across age groups in ways that can be partially rationalized in terms of exposure histories. Mutations that were fixed in influenza variants after 2020 cause greater escape from sera from younger individuals compared with adults. Overall, these results demonstrate that influenza faces distinct antigenic selection regimes from different age groups and suggest approaches to understand how this heterogeneous selection shapes viral evolution.

人类流感病毒不断进化,以逃避多克隆抗体的中和作用。然而,我们对病毒突变的抗原效应如何在人类群体中发生变化以及这种异质性如何影响病毒进化的了解十分有限。在这里,我们利用深度突变扫描绘制了两个H3N2毒株(A/香港/45/2019和A/柏斯/16/2009)的血凝素(HA)蛋白突变如何影响不同年龄个体血清中和病毒的图谱。HA突变对不同年龄组血清中和作用的影响各不相同,这在一定程度上可以用接触史来解释。与成年人相比,2020 年后固定在流感变异株中的突变在年轻人血清中的逃逸率更高。总之,这些结果表明,不同年龄组的流感面临着不同的抗原选择机制,并提出了了解这种异质性选择如何影响病毒进化的方法。
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引用次数: 0
Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease 肠道线粒体扰动导致微生物群依赖性损伤和炎症性疾病鉴别基因特征
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-07-15 DOI: 10.1016/j.chom.2024.06.013

Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBDs). To understand how microbial-metabolic circuits contribute to intestinal injury, we disrupt mitochondrial function in the epithelium by deleting the mitochondrial chaperone, heat shock protein 60 (Hsp60Δ/ΔIEC). This metabolic perturbation causes self-resolving tissue injury. Regeneration is disrupted in the absence of the aryl hydrocarbon receptor (Hsp60Δ/ΔIEC;AhR−/−) involved in intestinal homeostasis or inflammatory regulator interleukin (IL)-10 (Hsp60Δ/ΔIEC;Il10−/−), causing IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60Δ/ΔIEC mice, highlighting bacterial control of metabolic injury. Colonizing GF Hsp60Δ/ΔIEC mice with the synthetic community OMM12 reveals expansion of metabolically flexible Bacteroides, and B. caecimuris mono-colonization recapitulates the injury. Transcriptional profiling of the metabolically impaired epithelium reveals gene signatures involved in oxidative stress (Ido1, Nos2, Duox2). These signatures are observed in samples from Crohn’s disease patients, distinguishing active from inactive inflammation. Thus, mitochondrial perturbation of the epithelium causes microbiota-dependent injury with discriminative inflammatory gene profiles relevant for IBD.

线粒体功能障碍与炎症性肠病(IBD)有关。为了了解微生物代谢回路如何导致肠道损伤,我们通过删除线粒体伴侣--热休克蛋白 60(Hsp60Δ/ΔIEC)来破坏上皮细胞的线粒体功能。这种新陈代谢扰动会导致组织损伤的自我修复。在缺乏参与肠道稳态的芳基烃受体(Hsp60Δ/ΔIEC;AhR-/-)或炎症调节因子白细胞介素(IL)-10(Hsp60Δ/ΔIEC;Il10-/-)的情况下,组织再生会受到破坏,从而导致类似 IBD 的病理变化。无菌(GF)Hsp60Δ/ΔIEC 小鼠的远端结肠不存在损伤,这突显了细菌对代谢损伤的控制。用合成群落 OMM12 对 GF Hsp60Δ/ΔIEC 小鼠进行定殖,发现代谢灵活的乳酸杆菌扩增,而粪肠球菌的单一定殖再现了损伤。代谢受损上皮细胞的转录谱分析揭示了涉及氧化应激的基因特征(Ido1、Nos2、Duox2)。在克罗恩病患者的样本中也能观察到这些特征,从而区分活动性和非活动性炎症。因此,上皮细胞的线粒体扰乱会导致微生物群依赖性损伤,并产生与 IBD 相关的可区分的炎症基因特征。
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引用次数: 0
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