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Suppressing neutrophil itaconate production attenuates Mycoplasma pneumoniae pneumonia. 抑制中性粒细胞产生伊它康酸可减轻肺炎支原体肺炎。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-05 DOI: 10.1371/journal.ppat.1012614
Cui Wang, Jun Wen, Zijun Yan, Yujun Zhou, Zhande Gong, Ying Luo, Zhenkui Li, Kang Zheng, Haijun Zhang, Nan Ding, Chuan Wang, Cuiming Zhu, Yimou Wu, Aihua Lei

Mycoplasma pneumoniae is a common cause of community-acquired pneumonia in which neutrophils play a critical role. Immune-responsive gene 1 (IRG1), responsible for itaconate production, has emerged as an important regulator of inflammation and infection, but its role during M. pneumoniae infection remains unknown. Here, we reveal that itaconate is an endogenous pro-inflammatory metabolite during M. pneumoniae infection. Irg1 knockout (KO) mice had lower levels of bacterial burden, lactate dehydrogenase (LDH), and pro-inflammatory cytokines compared with wild-type (WT) controls after M. pneumoniae infection. Neutrophils were the major cells producing itaconate during M. pneumoniae infection in mice. Neutrophil counts were positively correlated with itaconate concentrations in bronchoalveolar lavage fluid (BALF) of patients with severe M. pneumoniae pneumonia. Adoptive transfer of Irg1 KO neutrophils, or administration of β-glucan (an inhibitor of Irg1 expression), significantly attenuated M. pneumoniae pneumonia in mice. Mechanistically, itaconate impaired neutrophil bacterial killing and suppressed neutrophil apoptosis via inhibiting mitochondrial ROS. Moreover, M. pneumoniae induced Irg1 expression by activating NF-κB and STAT1 pathways involving TLR2. Our data thus identify Irg1/itaconate pathway as a potential therapeutic target for the treatment of M. pneumoniae pneumonia.

肺炎支原体是社区获得性肺炎的常见病因,中性粒细胞在其中发挥着关键作用。负责产生伊塔康酸的免疫反应基因 1(IRG1)已成为炎症和感染的重要调节因子,但它在肺炎支原体感染过程中的作用仍不清楚。在这里,我们揭示了它康酸是肺炎霉菌感染过程中的一种内源性促炎症代谢产物。与野生型(WT)对照组相比,Irg1基因敲除(KO)小鼠感染肺炎霉菌后的细菌负荷、乳酸脱氢酶(LDH)和促炎细胞因子水平较低。中性粒细胞是小鼠感染肺炎霉菌后产生伊他康酸的主要细胞。中性粒细胞数量与重症肺炎双球菌肺炎患者支气管肺泡灌洗液(BALF)中伊他康酸浓度呈正相关。采用Irg1 KO中性粒细胞转移或服用β-葡聚糖(Irg1表达抑制剂)可显著减轻小鼠的肺炎霉菌肺炎。从机理上讲,伊塔康酸可通过抑制线粒体 ROS 来削弱中性粒细胞对细菌的杀伤力并抑制中性粒细胞的凋亡。此外,肺炎霉菌通过激活涉及 TLR2 的 NF-κB 和 STAT1 通路诱导 Irg1 的表达。因此,我们的数据确定了 Irg1/itaconate 通路是治疗 M. pneumoniae 肺炎的潜在治疗靶点。
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引用次数: 0
Tissue specific innate immune responses impact viral infection in Drosophila. 组织特异性先天免疫反应对果蝇病毒感染的影响
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-04 DOI: 10.1371/journal.ppat.1012672
Elisha Segrist, Steven Miller, Beth Gold, Yue Li, Sara Cherry

All organisms sense and respond to pathogenic challenge. Tissue-specific responses are required to combat pathogens infecting distinct cell types. Cyclic dinucleotides (CDNs) are produced endogenously downstream of pathogen recognition or by pathogens themselves which bind to STING to activate NF-kB-dependent antimicrobial gene expression programs. It remains unknown whether there are distinct immune responses to CDNs in Drosophila tissues. Here, we investigated tissue specific CDN-STING responses and uncovered differences in gene-induction patterns across tissues that play important roles in viral infections. Using tissue-and cell-specific genetic studies we found that dSTING in the fat body controls CDN-induced expression of dSTING-regulated gene 1 (Srg1) but not dSTING-regulated gene 2 (Srg2) or 3 (Srg3). In contrast, the gastrointestinal tract largely controls expression of Srg2 and Srg3. We found that Srg3 is antiviral against the natural fly pathogen Drosophila C virus and the human arthropod-borne Rift Valley Fever virus (RVFV), but not other arthropod-borne viruses including Sindbis virus and dengue virus. Furthermore, we found that Srg3 has an important role in controlling RVFV infection of the ovary which has important implications in understanding vertical transmission of viruses and RVFV in mosquitoes. Overall, our study underscores the importance of tissue-specific responses in antiviral immunity and highlights the complex tissue regulation of the CDN-STING pathway.

所有生物都能感知并应对病原体的挑战。要对抗感染不同细胞类型的病原体,就需要有组织特异性反应。环状二核苷酸(CDNs)是在病原体识别下游或由病原体本身产生的内源性物质,它与 STING 结合激活 NF-kB 依赖性抗微生物基因表达程序。果蝇组织对 CDNs 是否有不同的免疫反应仍是未知数。在这里,我们研究了组织特异性 CDN-STING 反应,并发现了在病毒感染中发挥重要作用的不同组织基因诱导模式的差异。通过组织和细胞特异性基因研究,我们发现脂肪体中的 dSTING 可控制 CDN 诱导的 dSTING 调节基因 1(Srg1)的表达,但不能控制 dSTING 调节基因 2(Srg2)或 3(Srg3)的表达。相反,胃肠道在很大程度上控制着 Srg2 和 Srg3 的表达。我们发现,Srg3 对天然蝇类病原体果蝇 C 病毒和人类节肢动物传播的裂谷热病毒(RVFV)有抗病毒作用,但对其他节肢动物传播的病毒(包括辛比病毒和登革热病毒)没有抗病毒作用。此外,我们还发现 Srg3 在控制 RVFV 感染卵巢方面起着重要作用,这对了解病毒和 RVFV 在蚊子中的垂直传播具有重要意义。总之,我们的研究强调了组织特异性反应在抗病毒免疫中的重要性,并突出了 CDN-STING 通路的复杂组织调控。
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引用次数: 0
CD4+ but not CD8+ T cells are required for protection against severe guinea pig cytomegalovirus infections. 豚鼠巨细胞病毒重症感染需要 CD4+ 而非 CD8+ T 细胞的保护。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-04 DOI: 10.1371/journal.ppat.1012515
Tyler B Rollman, Zachary W Berkebile, Dustin M Hicks, Jason S Hatfield, Priyanka Chauhan, Marco Pravetoni, Mark R Schleiss, Gregg N Milligan, Terry K Morgan, Craig J Bierle

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus and the leading cause of infectious disease related birth defects worldwide. How the immune response modulates the risk of intrauterine transmission of HCMV after maternal infection remains poorly understood. Maternal T cells likely play a critical role in preventing infection at the maternal-fetal interface and limiting spread across the placenta, but concerns exist that immune responses to infection may also cause placental dysfunction and adverse pregnancy outcomes. This study investigated the role of CD4+ and CD8+ T cells in a guinea pig model of primary cytomegalovirus infection. Monoclonal antibodies specific to guinea pig CD4 and CD8 were used to deplete T cells in non-pregnant and in pregnant guinea pigs after mid-gestation. CD4+ T cell depletion increased the severity of illness, caused significantly elevated viral loads, and increased the rate of congenital guinea pig cytomegalovirus (GPCMV) infection relative to animals treated with control antibody. CD8+ T cell depletion was comparably well tolerated and did not significantly affect the weight of infected guinea pigs or viral loads in their blood or tissue. However, significantly more viral genomes and transcripts were detected in the placenta and decidua of CD8+ T cell depleted dams post-infection. This study corroborates earlier findings made in nonhuman primates that maternal CD4+ T cells play a critical role in limiting the severity of primary CMV infection during pregnancy while also revealing that other innate and adaptive immune responses can compensate for an absent CD8+ T cell response in α-CD8-treated guinea pigs.

人类巨细胞病毒(HCMV)是一种无处不在的疱疹病毒,也是导致全球与传染病相关的出生缺陷的主要原因。人们对母体感染后免疫反应如何调节 HCMV 宫内传播风险仍知之甚少。母体 T 细胞在防止母胎界面感染和限制胎盘传播方面可能起着关键作用,但人们担心,对感染的免疫反应也可能导致胎盘功能障碍和不良妊娠结局。本研究调查了 CD4+ 和 CD8+ T 细胞在豚鼠原发性巨细胞病毒感染模型中的作用。在妊娠中期后,使用豚鼠 CD4 和 CD8 特异性单克隆抗体消耗非妊娠豚鼠和妊娠豚鼠的 T 细胞。与使用对照抗体的动物相比,CD4+ T细胞耗竭会增加疾病的严重程度,导致病毒载量显著升高,并增加先天性豚鼠巨细胞病毒(GPCMV)感染率。CD8+ T 细胞耗竭的耐受性相当好,对受感染豚鼠的体重或其血液或组织中的病毒载量没有显著影响。然而,在感染后CD8+ T细胞耗竭的母鼠胎盘和蜕膜中检测到的病毒基因组和转录本明显增多。这项研究证实了早先在非人灵长类动物身上的发现,即母体 CD4+ T 细胞在限制妊娠期原发性 CMV 感染的严重程度方面起着至关重要的作用,同时也揭示了其他先天性和适应性免疫反应可以补偿经 α-CD8 处理的豚鼠体内 CD8+ T 细胞反应的缺失。
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引用次数: 0
Adaptation of Candida albicans to specific host environments by gain-of-function mutations in transcription factors. 通过转录因子的功能增益突变使白色念珠菌适应特定宿主环境。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-04 eCollection Date: 2024-11-01 DOI: 10.1371/journal.ppat.1012643
Joachim Morschhäuser

The yeast Candida albicans is usually a harmless member of the normal microbiota in healthy persons but is also a major fungal pathogen that can colonize and infect almost every human tissue. A successful adaptation to environmental changes encountered in different host niches requires an appropriate regulation of gene expression. The zinc cluster transcription factors are the largest family of transcriptional regulators in C. albicans and are involved in the control of virtually all aspects of its biology. Under certain circumstances, mutations in these transcription factors that alter their activity and the expression of their target genes confer a selective advantage, which results in the emergence of phenotypically altered variants that are better adapted to new environmental challenges. This review describes how gain-of-function mutations in different zinc cluster transcription factors enable C. albicans to overcome antifungal therapy and to successfully establish itself in specific host niches.

白色念珠菌酵母通常是健康人正常微生物群中无害的一员,但也是一种主要的真菌病原体,几乎可以定殖和感染所有人体组织。要成功地适应不同宿主生境中遇到的环境变化,需要对基因表达进行适当的调控。锌簇转录因子是白僵菌中最大的转录调节因子家族,参与控制白僵菌生物学的几乎所有方面。在某些情况下,这些转录因子的突变会改变其活性及其靶基因的表达,从而带来选择性优势,导致出现表型改变的变体,更好地适应新的环境挑战。这篇综述介绍了不同锌簇转录因子的功能增益突变如何使白僵菌克服抗真菌治疗,并成功地在特定的宿主环境中立足。
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引用次数: 0
Copper acquisition is essential for plant colonization and virulence in a root-infecting vascular wilt fungus. 铜的获取对根部感染维管束枯萎病真菌的植物定殖和毒力至关重要。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-04 DOI: 10.1371/journal.ppat.1012671
Rafael Palos-Fernández, María Victoria Aguilar-Pontes, Gema Puebla-Planas, Harald Berger, Lena Studt-Reinhold, Joseph Strauss, Antonio Di Pietro, Manuel Sánchez López-Berges

Plant pathogenic fungi provoke devastating agricultural losses and are difficult to control. How these organisms acquire micronutrients during growth in the host environment remains poorly understood. Here we show that efficient regulation of copper acquisition mechanisms is crucial for plant colonization and virulence in the soilborne ascomycete Fusarium oxysporum, the causal agent of vascular wilt disease in more than 150 different crops. Using a combination of RNA-seq and ChIP-seq, we establish a direct role of the transcriptional regulator Mac1 in activation of copper deficiency response genes, many of which are induced during plant infection. Loss of Mac1 impaired growth of F. oxysporum under low copper conditions and abolishes pathogenicity on tomato plants and on the invertebrate animal host Galleria mellonella. Importantly, overexpression of two Mac1 target genes encoding a copper reductase and a copper transporter was sufficient to restore virulence in the mac1 mutant background. Our results establish a previously unrecognized role of copper reduction and uptake in fungal infection of plants and reveal new ways to protect crops from phytopathogens.

植物病原真菌会给农业造成毁灭性损失,而且难以控制。人们对这些生物在宿主环境中生长期间如何获取微量营养元素仍然知之甚少。在这里,我们发现铜获取机制的有效调控对于土传子囊菌 Fusarium oxysporum 的植物定殖和毒力至关重要,Fusarium oxysporum 是 150 多种作物维管束枯萎病的病原菌。通过结合使用 RNA-seq 和 ChIP-seq 技术,我们确定了转录调节因子 Mac1 在激活铜缺乏响应基因中的直接作用,其中许多基因在植物感染期间被诱导。缺失 Mac1 会影响 F. oxysporum 在低铜条件下的生长,并削弱其在番茄植株和无脊椎动物宿主 Galleria mellonella 上的致病性。重要的是,过表达编码铜还原酶和铜转运体的两个 Mac1 靶基因足以恢复 mac1 突变体背景下的致病性。我们的研究结果证实了铜还原和吸收在真菌感染植物过程中的作用,并揭示了保护农作物免受植物病原体侵害的新方法。
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引用次数: 0
B cell receptor dependent enhancement of dengue virus infection. B 细胞受体依赖性增强登革热病毒感染。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-31 DOI: 10.1371/journal.ppat.1012683
Chad Gebo, Céline S C Hardy, Benjamin D McElvany, Nancy R Graham, Joseph Q Lu, Shima Moradpour, Jeffrey R Currier, Heather Friberg, Gregory D Gromowski, Stephen J Thomas, Gary C Chan, Sean A Diehl, Adam T Waickman

Dengue virus (DENV) is the causative agent of dengue, a mosquito-borne disease that represents a significant and growing public health burden around the world. A unique pathophysiological feature of dengue is immune-mediated enhancement, wherein preexisting immunity elicited by a primary infection can enhance the severity of a subsequent infection by a heterologous DENV serotype. A leading mechanistic explanation for this phenomenon is antibody dependent enhancement (ADE), where sub-neutralizing concentrations of DENV-specific IgG antibodies facilitate entry of DENV into FcγR expressing cells such as monocytes, macrophages, and dendritic cells. Accordingly, this model posits that phagocytic mononuclear cells are the primary reservoir of DENV. However, analysis of samples from individuals experiencing acute DENV infection reveals that B cells are the largest reservoir of infected circulating cells, representing a disconnect in our understanding of immune-mediated DENV tropism. In this study, we demonstrate that the expression of a DENV-specific B cell receptor (BCR) renders cells highly susceptible to DENV infection, with the infection-enhancing activity of the membrane-restricted BCR correlating with the ADE potential of the IgG version of the antibody. In addition, we observed that the frequency of DENV-infectible B cells increases in previously flavivirus-naïve volunteers after a primary DENV infection. These findings suggest that BCR-dependent infection of B cells is a novel mechanism immune-mediated enhancement of DENV-infection.

登革热病毒(DENV)是登革热的病原体,登革热是一种由蚊子传播的疾病,对全世界的公共卫生造成了日益严重的负担。登革热的一个独特病理生理学特征是免疫介导的增强,即原发感染引起的原有免疫力会增强异源登革热病毒血清型后续感染的严重程度。对这一现象的主要机理解释是抗体依赖性增强(ADE),即亚中和浓度的 DENV 特异性 IgG 抗体可促进 DENV 进入 FcγR 表达细胞,如单核细胞、巨噬细胞和树突状细胞。因此,该模型认为吞噬性单核细胞是 DENV 的主要贮存库。然而,对急性 DENV 感染者样本的分析表明,B 细胞是最大的受感染循环细胞库,这表明我们对免疫介导的 DENV 趋向性的理解出现了脱节。在这项研究中,我们证明了 DENV 特异性 B 细胞受体(BCR)的表达使细胞极易感染 DENV,膜限制性 BCR 的感染增强活性与抗体 IgG 版本的 ADE 潜力相关。此外,我们还观察到,以前对黄病毒免疫的志愿者在初次感染 DENV 后,其可被 DENV 感染的 B 细胞的频率会增加。这些发现表明,B细胞的BCR依赖性感染是免疫介导的增强DENV感染的一种新机制。
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引用次数: 0
From acute to persistent infection: revealing phylogenomic variations in Salmonella Agona. 从急性感染到持续感染:揭示阿戈纳沙门氏菌的系统发育变异。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-31 DOI: 10.1371/journal.ppat.1012679
Emma V Waters, Winnie W Y Lee, Amina Ismail Ahmed, Marie-Anne Chattaway, Gemma C Langridge

Salmonella enterica serovar Agona (S. Agona) has been increasingly recognised as a prominent cause of gastroenteritis. This serovar is a strong biofilm former that can undergo genome rearrangement and enter a viable but non-culturable state whilst remaining metabolically active. Similar strategies are employed by S. Typhi, the cause of typhoid fever, during human infection, which are believed to assist with the transition from acute infection to chronic carriage. Here we report S. Agona's ability to persist in people and examine factors that might be contributing to chronic carriage. A review of 2233 S. Agona isolates from UK infections (2004-2020) and associated carriage was undertaken, in which 1155 had short-read sequencing data available. A subset of 207 isolates was selected from different stages of acute and persistent infections within individual patients. The subset underwent long-read sequencing and genome structure (GS) analysis, as well as phenotyping assays including carbon source utilisation and biofilm formation. Associations between genotypes and phenotypes were investigated to compare acute infections to those which progress to chronic. GS analysis revealed the conserved arrangement GS1.0 in 195 isolates, and 8 additional GSs in 12 isolates. These rearranged isolates were typically associated with early, convalescent carriage (3 weeks- 3 months). We also identified an increase in SNP variation during this period of infection. We believe this increase in genome-scale and SNP variation reflects a population expansion after acute S. Agona infection, potentially reflecting an immune evasion mechanism which enables persistent infection to become established.

越来越多的人认识到,肠炎沙门氏菌血清阿戈纳菌(S. Agona)是导致肠胃炎的主要原因。阿戈纳沙门氏菌具有很强的生物膜形成能力,可进行基因组重排,进入可存活但不可培养的状态,同时保持新陈代谢活跃。伤寒杆菌(伤寒的病原体)在人类感染期间也采用了类似的策略,这被认为有助于从急性感染过渡到慢性携带。在此,我们报告了阿戈纳氏菌在人体内的存活能力,并研究了可能导致慢性携带的因素。我们对来自英国感染(2004-2020 年)和相关携带的 2233 株阿戈纳氏菌分离物进行了回顾,其中 1155 株有短线程测序数据。从个别患者的急性和持续感染的不同阶段选取了 207 个分离物子集。该子集进行了长线程测序和基因组结构(GS)分析,以及表型检测,包括碳源利用和生物膜形成。研究了基因型和表型之间的关联,以比较急性感染和发展为慢性感染的情况。GS 分析表明,195 个分离物中有 GS1.0 的保守排列,12 个分离物中有 8 个额外的 GS。这些重新排列的分离株通常与早期、恢复期(3 周至 3 个月)的携带有关。我们还发现,在这一感染时期,SNP 变异有所增加。我们认为,基因组规模和 SNP 变异的增加反映了急性 S. Agona 感染后的种群扩张,可能反映了一种免疫逃避机制,这种机制使持续感染得以确立。
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引用次数: 0
A novel esterase regulates Klebsiella pneumoniae hypermucoviscosity and virulence. 一种新型酯酶可调节肺炎克雷伯氏菌的高黏度和毒力。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-31 DOI: 10.1371/journal.ppat.1012675
Lijun Wang, Zhe Wang, Hua Zhang, Qian Jin, Shuaihua Fan, Yanni Liu, Xueting Huang, Jun Guo, Chao Cai, Jing-Ren Zhang, Hui Wu

Klebsiella pneumoniae, an emerging multidrug-resistant pathogen, exhibits hypermucoviscosity (HMV) as a critical virulence trait mediated by its capsular polysaccharide (CPS). Recent discoveries have determined acetylation as a significant modification for CPS, although its impact on HMV and virulence was previously unknown. This study elucidates the roles of two enzymes: Klebsiella pneumoniae Acetylated CPS Esterase (KpACE), an esterase that removes acetyl groups from CPS, and WcsU, an acetyltransferase that adds acetyl groups to CPS. KpACE is highly upregulated in an ompR-deficient mutant lacking HMV, and its overexpression consistently reduces HMV and diminishes virulence in a mouse model of pneumonia. The esterase domain-containing KpACE effectively deacetylates model sugar substrates and CPS-K2. Site-directed mutagenesis of the conserved catalytic histidine residue at position 370 significantly reduces its enzymatic activity. This reduction correlates with decreased HMV, affecting key virulence traits including biofilm formation and serum resistance. Similarly, a deficiency in the wcsU gene abolishes CPS acetylation, and reduces HMV and virulence. These results highlight the importance of the delicate balance between CPS acetylation by WcsU and deacetylation by KpACE in regulating the pathogenicity of K. pneumoniae. Understanding this balance provides new insights into the modulation of virulence traits and potential therapeutic targets for combating K. pneumoniae infections.

肺炎克雷伯氏菌是一种新出现的耐多药病原体,它的高黏度(HMV)是由其荚膜多糖(CPS)介导的关键毒力特征。最近的研究发现,乙酰化是 CPS 的一种重要修饰,但乙酰化对 HMV 和毒力的影响以前尚不清楚。本研究阐明了两种酶的作用:肺炎克雷伯菌乙酰化 CPS 酯酶(KpACE)是一种酯酶,可从 CPS 上去除乙酰基;WcsU 是一种乙酰转移酶,可将乙酰基添加到 CPS 上。在缺乏 HMV 的 ompR 缺失突变体中,KpACE 高度上调;在肺炎小鼠模型中,KpACE 的过表达可持续减少 HMV 并降低毒力。含酯酶结构域的 KpACE 能有效地使模型糖底物和 CPS-K2 去乙酰化。对位于 370 位的保守催化组氨酸残基进行定点突变可显著降低其酶活性。酶活性的降低与 HMV 的降低相关,影响了包括生物膜形成和血清抗性在内的关键毒力特征。同样,wcsU 基因的缺失也会导致 CPS 乙酰化消失,并降低 HMV 和毒力。这些结果凸显了 WcsU 的 CPS 乙酰化和 KpACE 的去乙酰化之间的微妙平衡在调节肺炎双球菌致病性中的重要性。对这种平衡的理解为肺炎克氏菌毒力特征的调控和潜在的治疗靶点提供了新的见解。
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引用次数: 0
Dynamic composition of stress granules in Trypanosoma brucei. 布氏锥虫应激颗粒的动态组成
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-31 DOI: 10.1371/journal.ppat.1012666
Htay Mon Aye, Feng-Jun Li, Cynthia Y He

Stress granules (SGs) are stress-induced RNA condensates consisting of stalled initiation complexes resulting from translational inhibition. The biochemical composition and function of SGs are highly diverse, and this diversity has been attributed to different stress conditions, signalling pathways involved and specific cell types. Interestingly, mRNA decay components, which are found in ubiquitous cytoplasmic foci known as processing bodies (PB), have also been identified in SG proteomes. A major challenge in current SG studies is to understand the cause of SG diversity, as well as the function of SG under different stress conditions. Trypanosoma brucei is a single-cellular parasite that causes Human African Trypanosomiasis (sleping sickness). In this study, we showed that by varying the supply of extracellular carbon sources during starvation, cellular ATP levels changed rapidly, resulting in SGs of different compositions and dynamics. We identified a subset of SG components, which dissociated from the SGs in response to cellular ATP depletion. Using expansion microscopy, we observed sub-granular compartmentalization of PB- and SG-components within the stress granules. Our results highlight the importance of cellular ATP in SG composition and dynamics, providing functional insight to SGs formed under different stress conditions.

应激颗粒(SGs)是应激诱导的 RNA 凝聚物,由因翻译抑制而停滞的起始复合物组成。应激颗粒的生化组成和功能多种多样,这种多样性可归因于不同的应激条件、所涉及的信号通路和特定的细胞类型。有趣的是,在被称为加工体(PB)的无处不在的细胞质病灶中发现的 mRNA 衰减成分也在 SG 蛋白组中被发现。目前 SG 研究的一大挑战是了解 SG 多样性的原因以及 SG 在不同应激条件下的功能。布氏锥虫(Trypanosoma brucei)是一种单细胞寄生虫,可导致人类非洲锥虫病(sleping sickness)。在这项研究中,我们发现在饥饿状态下,通过改变细胞外碳源的供应,细胞内的 ATP 水平会迅速发生变化,从而产生不同组成和动态的 SG。我们发现了一部分 SG 成分,它们在细胞 ATP 枯竭时从 SG 中分离出来。利用膨胀显微镜,我们观察到了应力颗粒内 PB 和 SG 成分的亚颗粒区隔。我们的研究结果突显了细胞 ATP 在 SG 组成和动态中的重要性,为在不同应激条件下形成的 SG 提供了功能性见解。
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引用次数: 0
Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-γ induced IRF1. 代谢重编程通过稳定干扰素-γ诱导的IRF1来提示疫苗病毒感染的结果。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-30 DOI: 10.1371/journal.ppat.1012673
Tyron Chang, Jessica Alvarez, Sruthi Chappidi, Stacey Crockett, Mahsa Sorouri, Robert C Orchard, Dustin C Hancks

Interferon (IFN) induced activities are critical, early determinants of immune responses and infection outcomes. A key facet of IFN responses is the upregulation of hundreds of mRNAs termed interferon-stimulated genes (ISGs) that activate intrinsic and cell-mediated defenses. While primary interferon signaling is well-delineated, other layers of regulation are less explored but implied by aberrant ISG expression signatures in many diseases in the absence of infection. Consistently, our examination of tonic ISG levels across uninfected human tissues and individuals revealed three ISG subclasses. As tissue identity and many comorbidities with increased virus susceptibility are characterized by differences in metabolism, we characterized ISG responses in cells grown in media known to favor either aerobic glycolysis (glucose) or oxidative phosphorylation (galactose supplementation). While these conditions over time had a varying impact on the expression of ISG RNAs, the differences were typically greater between treatments than between glucose/galactose. Interestingly, extended interferon-priming led to divergent expression of two ISG proteins: upregulation of IRF1 in IFN-γ/glucose and increased IFITM3 in galactose by IFN-α and IFN-γ. In agreement with a hardwired response, glucose/galactose regulation of interferon-γ induced IRF1 is conserved in unrelated mouse and cat cell types. In galactose conditions, proteasome inhibition restored interferon-γ induced IRF1 levels to that of glucose/interferon-γ. Glucose/interferon-γ decreased replication of the model poxvirus vaccinia at low MOI and high MOIs. Vaccinia replication was restored by IRF1 KO. In contrast, but consistent with differential regulation of IRF1 protein by glucose/galactose, WT and IRF1 KO cells in galactose media supported similar levels of vaccinia replication regardless of IFN-γ priming. Also associated with glucose/galactose is a seemingly second block at a very late stage in viral replication which results in reductions in herpes- and poxvirus titers but not viral protein expression. Collectively, these data illustrate a novel layer of regulation for the key ISG protein, IRF1, mediated by glucose/galactose and imply unappreciated subprograms embedded in the interferon response. In principle, such cellular circuitry could rapidly adapt immune responses by sensing changing metabolite levels consumed during viral replication and cell proliferation.

干扰素(IFN)的诱导活动是免疫反应和感染结果的关键性早期决定因素。IFN 反应的一个关键方面是上调数百种被称为干扰素刺激基因(ISG)的 mRNA,从而激活内在和细胞介导的防御功能。虽然初级干扰素信号传导已被明确界定,但其他层次的调控却鲜有探索,但许多疾病在没有感染的情况下都会出现异常的 ISG 表达特征。同样,我们对未感染人体组织和个体的强直性 ISG 水平的研究发现了三种 ISG 亚类。由于组织特征和许多病毒易感性增加的合并症都以新陈代谢的差异为特征,我们对在已知有利于有氧糖酵解(葡萄糖)或氧化磷酸化(补充半乳糖)的培养基中生长的细胞的 ISG 反应进行了研究。虽然随着时间的推移,这些条件对 ISG RNA 的表达产生了不同的影响,但不同处理之间的差异通常大于葡萄糖/半乳糖之间的差异。有趣的是,延长干扰素诱导会导致两种 ISG 蛋白的不同表达:在 IFN-γ/ 葡萄糖中,IRF1 上调;而在半乳糖中,IFITM3 在 IFN-α 和 IFN-γ 的作用下增加。葡萄糖/半乳糖对干扰素-γ诱导的IRF1的调节在无关的小鼠和猫细胞类型中是一致的,这与硬连接反应一致。在半乳糖条件下,蛋白酶体抑制可使干扰素-γ诱导的IRF1水平恢复到葡萄糖/干扰素-γ的水平。葡萄糖/干扰素-γ在低MOI和高MOI下都能减少模式痘病毒疫苗的复制。IRF1 KO 可恢复疫苗病毒的复制。相反,但与葡萄糖/半乳糖对 IRF1 蛋白的不同调节作用一致的是,无论 IFN-γ 是否起效,WT 和 IRF1 KO 细胞在半乳糖培养基中支持相似水平的疫苗病毒复制。同样与葡萄糖/半乳糖相关的是病毒复制后期似乎出现的第二个阻滞,它导致疱疹病毒和痘病毒滴度降低,但病毒蛋白表达却没有降低。总之,这些数据说明了由葡萄糖/半乳糖介导的对关键 ISG 蛋白 IRF1 的新的调节层,并暗示了干扰素反应中未被重视的子程序。原则上,这种细胞回路可以通过感知病毒复制和细胞增殖过程中消耗的代谢物水平的变化,迅速调整免疫反应。
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