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Bipolaris or Curvularia? Resolving the spicy issue of how clinical isolates should be reported.
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-20 eCollection Date: 2024-11-01 DOI: 10.1371/journal.ppat.1012678
Sarah E Kidd, Lars F Westblade
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引用次数: 0
Enterovirus A71 and coxsackievirus A6 circulation in England, UK, 2006-2017: A mathematical modelling study using cross-sectional seroprevalence data. 2006-2017 年英国英格兰肠道病毒 A71 和柯萨奇病毒 A6 的流行情况:利用横断面血清流行率数据进行的数学建模研究。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-20 eCollection Date: 2024-11-01 DOI: 10.1371/journal.ppat.1012703
Everlyn Kamau, Ben Lambert, David J Allen, Cristina Celma, Stuart Beard, Heli Harvala, Peter Simmonds, Nicholas C Grassly, Margarita Pons-Salort

Enterovirus A71 (EV-A71) and coxsackievirus A6 (CVA6) primarily cause hand, foot and mouth disease and have emerged to cause potential fatal neurological and systemic manifestations. However, limited surveillance data collected through passive surveillance systems hampers characterization of their epidemiological dynamics. We fit a series of catalytic models to age-stratified seroprevalence data for EV-A71 and CVA6 collected in England at three time points (2006, 2011 and 2017) to estimate the force of infection (FOI) over time and assess possible changes in transmission. For both serotypes, model comparison does not support the occurrence of important changes in transmission over the study period, and we find that a declining risk of infection with age and / or seroreversion are needed to explain the seroprevalence data. Furthermore, we provide evidence that the increased number of reports of CVA6 during 2006-2017 is unlikely to be explained by changes in surveillance. Therefore, we hypothesize that the increased number of CVA6 cases observed since 2011 must be explained by increased virus pathogenicity. Further studies of seroprevalence data from other countries would allow to confirm this. Our results underscore the value of seroprevalence data to unravel changes in the circulation dynamics of pathogens with weak surveillance systems and large number of asymptomatic infections.

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引用次数: 0
TMPRSS2 in microbial interactions: Insights from HKU1 and TcsH.
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-20 eCollection Date: 2024-11-01 DOI: 10.1371/journal.ppat.1012677
Zhengyang Pan, Daoqun Li, Leiliang Zhang

Transmembrane Serine Protease 2 (TMPRSS2), known primarily for its role as a protease, has emerged as a critical receptor for microbial agents such as human coronavirus HKU1 and exotoxin TcsH. HKU1 utilizes both sialoglycan and TMPRSS2 for cellular entry, where sialoglycan primes the spike protein for TMPRSS2 binding. TMPRSS2 undergoes autocleavage to enhance its affinity for the HKU1 spike, facilitating viral membrane fusion postcleavage. Interestingly, TMPRSS2's catalytic function is dispensable for both HKU1 and TcsH interactions, suggesting alternative roles in pathogenesis. Structural insights highlight potential therapeutic targets against viral infections and cancers, leveraging TMPRSS2 interactions for drug development. Understanding the interplay between TMPRSS2 and microbes opens new avenues for targeting TMPRSS2 in developing treatments for infections.

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引用次数: 0
The Cryptococcus neoformans STRIPAK complex controls genome stability, sexual development, and virulence. 新型隐球菌 STRIPAK 复合物控制着基因组稳定性、有性发育和毒力。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-19 DOI: 10.1371/journal.ppat.1012735
Patricia P Peterson, Jin-Tae Choi, Ci Fu, Leah E Cowen, Sheng Sun, Yong-Sun Bahn, Joseph Heitman

The eukaryotic serine/threonine protein phosphatase PP2A is a heterotrimeric enzyme composed of a scaffold A subunit, a regulatory B subunit, and a catalytic C subunit. Of the four known B subunits, the B"' subunit (known as striatin) interacts with the multi-protein striatin-interacting phosphatase and kinase (STRIPAK) complex. Orthologs of STRIPAK components were identified in Cryptococcus neoformans, namely PP2AA/Tpd3, PP2AC/Pph22, PP2AB/Far8, STRIP/Far11, SLMAP/Far9, and Mob3. Structural modeling, protein domain analysis, and detected protein-protein interactions suggest C. neoformans STRIPAK is assembled similarly to the human and fungal orthologs. Here, STRIPAK components Pph22, Far8, and Mob3 were functionally characterized. Whole-genome sequencing revealed that mutations in STRIPAK complex subunits lead to increased segmental and chromosomal aneuploidy, suggesting STRIPAK functions in maintaining genome stability. We demonstrate that PPH22 is a haploinsufficient gene: heterozygous PPH22/pph22Δ mutant diploid strains exhibit defects in hyphal growth and sporulation and have a significant fitness disadvantage when grown in competition against a wild-type diploid. Deletion mutants pph22Δ, far8Δ, and mob3Δ exhibit defects in mating and sexual differentiation, including impaired hyphae, basidia, and basidiospore production. Loss of either PPH22 or FAR8 in a haploid background leads to growth defects at 30°C, severely reduced growth at elevated temperature, abnormal cell morphology, and impaired virulence. Additionally, pph22Δ strains frequently accumulate suppressor mutations that result in overexpression of another putative PP2A catalytic subunit, PPG1. The pph22Δ and far8Δ mutants are also unable to grow in the presence of the calcineurin inhibitors cyclosporine A or FK506, and thus these mutations are synthetically lethal with loss of calcineurin activity. Conversely, mob3Δ mutants display increased thermotolerance, capsule production, and melanization, and are hypervirulent in a murine infection model. Taken together, these findings reveal that the C. neoformans STRIPAK complex plays an important role in genome stability, vegetative growth, sexual development, and virulence in this prominent human fungal pathogen.

真核丝氨酸/苏氨酸蛋白磷酸酶 PP2A 是一种异源三聚体酶,由支架 A 亚基、调节 B 亚基和催化 C 亚基组成。在已知的四个 B 亚基中,B"'亚基(称为纹蛋白)与多蛋白质纹蛋白相互作用磷酸酶和激酶(STRIPAK)复合物相互作用。在新生隐球菌中发现了 STRIPAK 成分的同源物,即 PP2AA/Tpd3、PP2AC/Pph22、PP2AB/Far8、STRIP/Far11、SLMAP/Far9 和 Mob3。结构建模、蛋白结构域分析和检测到的蛋白-蛋白相互作用表明,新畸形芽孢杆菌 STRIPAK 的组装方式与人类和真菌的直向同源物相似。本文对 STRIPAK 成分 Pph22、Far8 和 Mob3 进行了功能鉴定。全基因组测序发现,STRIPAK复合体亚基的突变会导致节段和染色体非整倍体增加,这表明STRIPAK具有维持基因组稳定性的功能。我们证明 PPH22 是一个单倍性不足的基因:杂合子 PPH22/pph22Δ 突变二倍体菌株表现出芽胞生长和孢子分裂缺陷,在与野生型二倍体竞争时处于明显的劣势。缺失突变体 pph22Δ、far8Δ 和 mob3Δ 在交配和有性分化方面表现出缺陷,包括菌丝、基原体和基原孢子生产受损。在单倍体背景下,缺失 PPH22 或 FAR8 会导致 30°C 生长缺陷、高温下生长严重减弱、细胞形态异常以及毒力减弱。此外,ph22Δ菌株经常积累抑制突变,导致另一种推定的 PP2A 催化亚基 PPG1 过表达。pph22Δ 和 far8Δ 突变体在钙调磷酸酶抑制剂环孢素 A 或 FK506 的存在下也无法生长,因此这些突变体在失去钙调磷酸酶活性的情况下是合成致死的。相反,mob3Δ突变体显示出更强的耐热性、胶囊生成和黑色化,并且在小鼠感染模型中具有很强的毒性。总之,这些发现揭示了新霉菌 STRIPAK 复合物在这一重要的人类真菌病原体的基因组稳定性、无性生殖、有性发育和毒力方面发挥着重要作用。
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引用次数: 0
Antagonism of BST2/Tetherin, a new restriction factor of respiratory syncytial virus, requires the viral NS1 protein. 呼吸道合胞病毒的一种新限制因子 BST2/Tetherin 的拮抗作用需要病毒 NS1 蛋白。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-19 DOI: 10.1371/journal.ppat.1012687
Katherine Marougka, Delphine Judith, Tristan Jaouen, Sabine Blouquit-Laye, Gina Cosentino, Clarisse Berlioz-Torrent, Marie-Anne Rameix-Welti, Delphine Sitterlin

Human respiratory syncytial virus (RSV) is an enveloped RNA virus and the leading viral agent responsible for severe pediatric respiratory infections worldwide. Identification of cellular factors able to restrict viral infection is one of the key strategies used to design new drugs against infection. Here, we report for the first time that the cellular protein BST2/Tetherin (a widely known host antiviral molecule) behaves as a restriction factor of RSV infection. We showed that BST2 silencing resulted in a significant rise in viral production during multi-cycle infection, suggesting an inhibitory role during the late steps of RSV's multiplication cycle. Conversely, BST2 overexpression resulted in diminution of the viral production. Furthermore, BST2 was found associated with envelope proteins and co-localized with viral filaments, suggesting that BST2 tethers RSV particles. Interestingly, RSV naturally downregulates cell surface and global BST2 expression, possibly through a mechanism dependent on ubiquitin. RSV's ability to enhance BST2 degradation was also validated in a model of differentiated cells infected by RSV. Additionally, we found that a virus deleted of NS1 is unable to downregulate BST2 and is significantly more susceptible to BST2 restriction compared to the wild type virus. Moreover, NS1 and BST2 interact in a co- immunoprecipitation experiment. Overall, our data support a model in which BST2 is a restriction factor against RSV infection and that the virus counteracts this effect by limiting the cellular factor's expression through a mechanism involving the viral protein NS1.

人类呼吸道合胞病毒(RSV)是一种包膜 RNA 病毒,是导致全球严重儿科呼吸道感染的主要病毒病原体。鉴定能够限制病毒感染的细胞因子是设计抗感染新药的关键策略之一。在这里,我们首次报道了细胞蛋白 BST2/Tetherin(一种广为人知的宿主抗病毒分子)是 RSV 感染的限制因子。我们发现,在多周期感染过程中,BST2沉默会导致病毒产量显著上升,这表明它在RSV繁殖周期的后期起着抑制作用。相反,BST2 过表达会导致病毒产量减少。此外,还发现 BST2 与包膜蛋白相关,并与病毒丝共定位,这表明 BST2 能拴住 RSV 颗粒。有趣的是,RSV 自然会下调细胞表面和全局 BST2 的表达,这可能是通过一种依赖于泛素的机制。RSV 增强 BST2 降解的能力也在 RSV 感染的分化细胞模型中得到了验证。此外,我们还发现,与野生型病毒相比,缺失 NS1 的病毒无法下调 BST2,而且更容易受到 BST2 的限制。此外,在共同免疫沉淀实验中,NS1 和 BST2 相互作用。总之,我们的数据支持这样一个模型,即 BST2 是抵抗 RSV 感染的限制因子,而病毒通过涉及病毒蛋白 NS1 的机制限制细胞因子的表达,从而抵消这种效应。
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引用次数: 0
AGC family kinase of Entamoeba histolytica: Decoding the members biochemically. 组织溶解性肠虫的 AGC 家族激酶:从生物化学角度解码其成员
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-19 DOI: 10.1371/journal.ppat.1012729
Azhar Ahmad, Vikas Kumar, Tushar Kushwaha, Akash Kumar, Deepak Sehgal, Krishna K Inampudi, Somlata

Entamoeba histolytica, a protozoan parasite, is the causative agent of amoebiasis, which is a significant global health concern. The virulence mechanisms underlying its pathogenicity are multifaceted and complex. However, endocytic processes and motility are well accepted virulence determinants. As previously reported, an AGCK family kinase, EhAGCK1 to be involved in trogocytosis exclusively while another one from same family named EhAGCK2 participates in all actin dependent endocytic processes. As the kinase dead mutants of EhAGCK1 showed significant defect in destruction of live host cells and also the localisation pattern of same is distinguishable from EhAGCK2. From observations so far, it appears that former initiates a distinguishable signaling cascade. In this work, we have demonstrated distinct biochemical properties of kinases involved in related yet distinguishable endocytic processes for the first time. Our biochemical characterization highlights distinct ion dependency of EhAGCK1 along with substrate specificity. We also show upstream activator of these kinases, 3-phosphoinositide dependent kinase 1 (PDK1) activity and its role in activating the kinase activity. The kinases exhibit property of autophosphorylation, and which may regulate the kinase activity subsequently. Summarily, these studies show that EhAGCK1 and EhAGCK2 show distinct biochemical properties which further confirm their unique role in related endocytic processes of trogocytosis and phagocytosis.

组织溶解恩塔米巴虫是一种原生动物寄生虫,是阿米巴病的病原体,对全球健康造成严重影响。其致病的毒力机制是多方面和复杂的。然而,内细胞过程和运动性是公认的致病决定因素。据先前报道,AGCK 家族激酶 EhAGCK1 只参与逆行细胞吞噬,而同族的另一个激酶 EhAGCK2 则参与所有肌动蛋白依赖性内吞过程。由于 EhAGCK1 的激酶死亡突变体在破坏活的宿主细胞方面表现出明显的缺陷,而且其定位模式也与 EhAGCK2 有所区别。从目前的观察结果来看,EhAGCK1 和 EhAGCK2 启动了不同的信号级联。在这项工作中,我们首次证明了参与相关但可区分的内细胞过程的激酶的不同生化特性。我们的生化鉴定突出了 EhAGCK1 对离子的依赖性以及底物的特异性。我们还展示了这些激酶的上游激活剂--3-磷酸肌醇依赖性激酶 1(PDK1)的活性及其在激活激酶活性中的作用。激酶表现出自身磷酸化的特性,这可能会随后调节激酶的活性。总之,这些研究表明,EhAGCK1 和 EhAGCK2 表现出不同的生化特性,进一步证实了它们在相关的逆向吞噬和吞噬细胞内吞过程中的独特作用。
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引用次数: 0
Sustained immune activation and impaired epithelial barrier integrity in the ectocervix of women with chronic HIV infection. 慢性 HIV 感染妇女宫颈的持续免疫激活和上皮屏障完整性受损。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-19 DOI: 10.1371/journal.ppat.1012709
Mathias Franzén Boger, Tyra Hasselrot, Vilde Kaldhusdal, Gisele H B Miranda, Paulo Czarnewski, Gabriella Edfeldt, Frideborg Bradley, Genta Rexaj, Julie Lajoie, Kenneth Omollo, Joshua Kimani, Keith R Fowke, Kristina Broliden, Annelie Tjernlund

Chronic systemic immune activation significantly influences human immunodeficiency virus (HIV) disease progression. Despite evidence of a pro-inflammatory environment in the genital tract of HIV-infected women, comprehensive investigations into cervical tissue from this region remain limited. Similarly, the consequences of chronic HIV infection on the integrity of the female genital epithelium are poorly understood, despite its importance in HIV transmission and replication. Ectocervical biopsies were obtained from HIV-seropositive (n = 14) and HIV-seronegative (n = 47) female Kenyan sex workers. RNA sequencing and bioimage analysis of epithelial junction proteins (E-cadherin, desmoglein-1, claudin-1, and zonula occludens-1) were conducted, along with CD4 staining. RNA sequencing revealed upregulation of immunoregulatory genes in HIV-seropositive women, primarily associated with heightened T cell activity and interferon signaling, which further correlated with plasma viral load. Transcription factor analysis confirmed the upregulation of pro-inflammatory transcription factors, such as RELA, NFKB1, and IKZF3, which facilitates HIV persistence in T cells. Conversely, genes and pathways associated with epithelial barrier function and structure were downregulated in the context of HIV. Digital bioimage analysis corroborated these findings, revealing significant disruption of various epithelial junction proteins in ectocervical tissues of the HIV-seropositive women. Thus, chronic HIV infection associated with ectocervical inflammation, characterized by induced T cell responses and interferon signaling, coupled with epithelial disruption. These alterations may influence HIV transmission and heighten susceptibility to other sexually transmitted infections. These findings prompt exploration of therapeutic interventions to address HIV-related complications and mitigate the risk of sexually transmitted infection transmission.

慢性全身免疫激活对人类免疫缺陷病毒(HIV)疾病的进展有很大影响。尽管有证据表明 HIV 感染女性的生殖道存在促炎环境,但对该区域宫颈组织的全面研究仍然有限。同样,尽管女性生殖器上皮在 HIV 传播和复制过程中非常重要,但人们对慢性 HIV 感染对其完整性的影响也知之甚少。我们从肯尼亚女性性工作者中获取了 HIV 血清阳性(14 人)和 HIV 阴性(47 人)的宫颈活检组织。对上皮连接蛋白(E-cadherin、desmoglein-1、claudin-1 和 zonula occludens-1)进行了 RNA 测序和生物图像分析,并进行了 CD4 染色。RNA 测序显示,HIV 血清阳性妇女体内的免疫调节基因上调,主要与 T 细胞活性增强和干扰素信号传导有关,并与血浆病毒载量进一步相关。转录因子分析证实了促炎症转录因子的上调,如 RELA、NFKB1 和 IKZF3,这有利于 HIV 在 T 细胞中的持续存在。相反,与上皮屏障功能和结构相关的基因和通路在 HIV 感染的情况下则出现下调。数字生物图像分析证实了这些发现,揭示了艾滋病毒血清阳性妇女宫颈组织中各种上皮连接蛋白的严重破坏。因此,HIV 慢性感染与宫颈炎症有关,宫颈炎症的特点是诱导 T 细胞反应和干扰素信号传导,并伴有上皮细胞破坏。这些改变可能会影响 HIV 的传播,并增加感染其他性传播疾病的几率。这些发现促使人们探索治疗干预措施,以解决与艾滋病相关的并发症,降低性传播感染的传播风险。
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引用次数: 0
Mucosal immunization with the lung Lactobacillus-derived amphiphilic exopolysaccharide adjuvanted recombinant vaccine improved protection against P. aeruginosa infection. 使用肺乳酸杆菌衍生的两亲性外多糖佐剂重组疫苗进行粘膜免疫可提高对铜绿假单胞菌感染的保护能力。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-18 DOI: 10.1371/journal.ppat.1012696
Haochi Zhang, Shouxin Sheng, Chunhe Li, Xuemei Bao, Lixia Zhao, Jian Chen, Pingyuan Guan, Xiaoyan Li, Na Pan, Yanchen Liang, Xueqi Wang, Jingmin Sun, Xiao Wang

Respiratory infections caused by Pseudomonas aeruginosa are a major health problem globally. Current treatment for P. aeruginosa infections relies solely on antibiotics, but the rise of antibiotic-resistant strains necessitates an urgent need for a protective vaccine. Traditional parenteral vaccines, despite employing potent adjuvants aimed at serotype-dependent immunity, often fail to elicit the desired mucosal immune response. Thus, developing vaccines that target both localized mucosal and systemic immune responses represents a promising direction for future research on P. aeruginosa vaccination. In this study, we explored EPS301, the exopolysaccharide derived from the lung microbiota strain Lactobacillus plantarum WXD301, which exhibits excellent self-assembly properties, enabling the formation of homogeneous nanoparticles when encapsulating recombinant PcrV of P. aeruginosa, designated as EPS301@rPcrV. Notably, the EPS301 vector effectively enhanced antigen adhesion to the nasal and pulmonary mucosal tissues and prolonged antigen retention. Moreover, EPS301@rPcrV provided effective and sustained protection against P. aeruginosa pneumonia, surpassing the durability achieved with the "gold standard" cholera toxin adjuvant. The EPS301-adjuvanted vaccine formulation elicited robust mucosal IgA and Th17/γδ17 T cell responses, which exceeded those induced by the CTB-adjuvanted vaccination and were sustained for over 112 days. Additionally, Th 17 and γδ 17 resident memory T cells induced by EPS301@rPcrV were crucial for protection against P. aeruginosa challenge. Intriguingly, IL-17A knockout mice exhibited lower survival rates, impaired bacterial clearance ability, and exacerbated lung tissue damage upon EPS301 adjuvanted vaccination against P. aeruginosa-induced pneumonia, indicating an IL-17A-dependent protective mechanism. In conclusion, our findings provided direct evidence that EPS301@rPcrV mucosal vaccine is a promising candidate for future clinical application against P. aeruginosa-induced pulmonary infection.

铜绿假单胞菌引起的呼吸道感染是全球主要的健康问题。目前治疗铜绿假单胞菌感染主要依靠抗生素,但随着抗生素耐药菌株的增多,迫切需要一种保护性疫苗。传统的肠外疫苗尽管使用了强效佐剂以获得血清型依赖性免疫,但往往无法引起理想的粘膜免疫反应。因此,开发同时针对局部粘膜和全身免疫反应的疫苗是未来铜绿假单胞菌疫苗接种研究的一个很有前景的方向。在本研究中,我们探索了从肺部微生物菌株植物乳杆菌 WXD301 中提取的外多糖 EPS301,它表现出优异的自组装特性,在包裹铜绿假单胞菌重组 PcrV 时可形成均质纳米颗粒,命名为 EPS301@rPcrV。值得注意的是,EPS301载体有效增强了抗原对鼻腔和肺部粘膜组织的粘附性,并延长了抗原的保留时间。此外,EPS301@rPcrV 还能有效、持续地预防铜绿假单胞菌肺炎,其持久性超过了 "黄金标准 "霍乱毒素佐剂。EPS301佐剂疫苗制剂可诱导出强健的粘膜IgA和Th17/γδ17 T细胞应答,这些应答超过了CTB佐剂疫苗接种所诱导的应答,并可持续112天以上。此外,EPS301@rPcrV诱导的Th 17和γδ17驻留记忆T细胞对铜绿假单胞菌挑战的保护至关重要。耐人寻味的是,IL-17A基因敲除小鼠在接种EPS301佐剂预防铜绿假单胞菌引起的肺炎时,存活率较低,细菌清除能力受损,肺组织损伤加剧,这表明IL-17A依赖性保护机制。总之,我们的研究结果提供了直接证据,证明EPS301@rPcrV粘膜疫苗是未来临床应用于抗击绿脓杆菌诱导的肺部感染的一种有前途的候选疫苗。
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引用次数: 0
The blast pathogen effector AVR-Pik binds and stabilizes rice heavy metal-associated (HMA) proteins to co-opt their function in immunity. 稻瘟病病原体效应物 AVR-Pik 与水稻重金属相关蛋白(HMA)结合并使其稳定,从而共同发挥其免疫功能。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-18 DOI: 10.1371/journal.ppat.1012647
Kaori Oikawa, Koki Fujisaki, Motoki Shimizu, Takumi Takeda, Keiichiro Nemoto, Hiromasa Saitoh, Akiko Hirabuchi, Yukie Hiraka, Naomi Miyaji, Aleksandra Białas, Thorsten Langner, Ronny Kellner, Tolga O Bozkurt, Stella Cesari, Thomas Kroj, Mark J Banfield, Sophien Kamoun, Ryohei Terauchi

Intracellular nucleotide-binding domain and leucine-rich repeat-containing (NLR) receptors play crucial roles in immunity across multiple domains of life. In plants, a subset of NLRs contain noncanonical integrated domains that are thought to have evolved from host targets of pathogen effectors to serve as pathogen baits. However, the functions of host proteins with similarity to NLR integrated domains and the extent to which they are targeted by pathogen effectors remain largely unknown. Here, we show that the blast fungus effector AVR-Pik binds a subset of related rice proteins containing a heavy metal-associated (HMA) domain, one of the domains that has repeatedly integrated into plant NLR immune receptors. We find that AVR-Pik binding stabilizes the rice small HMA (sHMA) proteins OsHIPP19 and OsHIPP20. Knockout of OsHIPP20 causes enhanced disease resistance towards the blast pathogen, indicating that OsHIPP20 is a susceptibility gene (S-gene). We propose that AVR-Pik has evolved to bind HMA domain proteins and co-opt their function to suppress immunity. Yet this binding carries a trade-off, it triggers immunity in plants carrying NLR receptors with integrated HMA domains.

细胞内核苷酸结合域和富含亮氨酸重复序列(NLR)受体在多个生命领域的免疫中发挥着至关重要的作用。在植物中,一部分 NLR 含有非规范整合结构域,这些结构域被认为是从病原体效应物的宿主靶标进化而来,可作为病原体的诱饵。然而,与 NLR 整合结构域相似的宿主蛋白质的功能以及它们在多大程度上成为病原体效应物的靶标,在很大程度上仍是未知数。在这里,我们发现稻瘟病真菌效应物 AVR-Pik 能与含有重金属相关(HMA)结构域的相关水稻蛋白质亚群结合,而重金属相关(HMA)结构域是反复整合到植物 NLR 免疫受体中的结构域之一。我们发现,AVR-Pik 的结合能稳定水稻小 HMA(sHMA)蛋白 OsHIPP19 和 OsHIPP20。敲除 OsHIPP20 会增强对稻瘟病病原体的抗病性,这表明 OsHIPP20 是一个易感基因(S 基因)。我们认为,AVR-Pik 在进化过程中结合了 HMA 结构域蛋白,并共同利用其功能来抑制免疫。然而,这种结合需要权衡利弊,它会在携带集成了 HMA 结构域的 NLR 受体的植物中触发免疫。
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引用次数: 0
Polyamines mediate cellular energetics and lipid metabolism through mitochondrial respiration to facilitate virus replication. 多胺通过线粒体呼吸介导细胞能量和脂质代谢,促进病毒复制。
IF 5.5 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-18 DOI: 10.1371/journal.ppat.1012711
Yazmin E Cruz-Pulido, Natalie J LoMascolo, Delaina May, Jomana Hatahet, Caroline E Thomas, Andrea K W Chu, Samantha P Stacey, Maria Del Mar Villanueva Guzman, Gregory Aubert, Bryan C Mounce

Polyamines are critical cellular components that regulate a variety of processes, including translation, cell cycling, and nucleic acid metabolism. The polyamines, putrescine, spermidine, and spermine, are found abundantly within cells and are positively-charged at physiological pH. Polyamine metabolism is connected to distinct other metabolic pathways, including nucleotide and amino acid metabolism. However, the breadth of the effect of polyamines on cellular metabolism remains to be fully understood. We recently demonstrated a role for polyamines in cholesterol metabolism, and following these studies, we measured the impact of polyamines on global lipid metabolism. We find that lipid droplets increase in number and size with polyamine depletion. We further demonstrate that lipid anabolism is markedly decreased, and lipid accumulation is due to reduced mitochondrial fatty acid oxidation. In fact, mitochondrial structure and function are largely ablated with polyamine depletion. To compensate, cells depleted of polyamines switch from aerobic respiration to glycolysis in a polyamine depletion-mediated Warburg-like effect. Finally, we show that inhibitors of lipid metabolism are broadly antiviral, suggesting that polyamines and lipids are promising antiviral targets. Together, these data demonstrate a novel role for polyamines in mitochondrial function, lipid metabolism, and cellular energetics.

多胺是调节翻译、细胞周期和核酸代谢等多种过程的重要细胞成分。多胺(腐胺、亚精胺和精胺)在细胞内含量丰富,在生理 pH 值下带正电荷。多胺代谢与核苷酸和氨基酸代谢等其他代谢途径密切相关。然而,多胺对细胞代谢影响的广度仍有待充分了解。我们最近证明了多胺在胆固醇代谢中的作用,继这些研究之后,我们测量了多胺对全球脂质代谢的影响。我们发现,脂滴的数量和大小会随着多胺的消耗而增加。我们进一步证明,脂质合成代谢明显降低,脂质积累是线粒体脂肪酸氧化作用降低所致。事实上,线粒体的结构和功能随着多胺的耗竭而在很大程度上消失。为了弥补这一缺陷,在多胺耗竭介导的类似沃伯格效应中,耗竭多胺的细胞从有氧呼吸转向糖酵解。最后,我们发现脂质代谢抑制剂具有广泛的抗病毒作用,这表明多胺和脂质是很有希望的抗病毒靶点。这些数据共同证明了多胺在线粒体功能、脂质代谢和细胞能量方面的新作用。
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引用次数: 0
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