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Methylation of KSHV vCyclin by PRMT5 contributes to cell cycle progression and cell proliferation PRMT5 对 KSHV vCyclin 的甲基化有助于细胞周期进展和细胞增殖
IF 6.7 1区 医学 Q1 Immunology and Microbiology Pub Date : 2024-09-10 DOI: 10.1371/journal.ppat.1012535
Danping Niu, Yuanming Ma, Pengyu Ren, Sijia Chang, Chenhui Li, Yong Jiang, Chunyan Han, Ke Lan
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus that encodes numerous cellular homologs, including cyclin D, G protein-coupled protein, interleukin-6, and macrophage inflammatory proteins 1 and 2. KSHV vCyclin encoded by ORF72, is the homolog of cellular cyclinD2. KSHV vCyclin can regulate virus replication and cell proliferation by constitutively activating cellular cyclin-dependent kinase 6 (CDK6). However, the regulatory mechanism of KSHV vCyclin has not been fully elucidated. In the present study, we identified a host protein named protein arginine methyltransferase 5 (PRMT5) that interacts with KSHV vCyclin. We further demonstrated that PRMT5 is upregulated by latency-associated nuclear antigen (LANA) through transcriptional activation. Remarkably, knockdown or pharmaceutical inhibition (using EPZ015666) of PRMT5 inhibited the cell cycle progression and cell proliferation of KSHV latently infected tumor cells. Mechanistically, PRMT5 methylates vCyclin symmetrically at arginine 128 and stabilizes vCyclin in a methyltransferase activity-dependent manner. We also show that the methylation of vCyclin by PRMT5 positively regulates the phosphorylate retinoblastoma protein (pRB) pathway. Taken together, our findings reveal an important regulatory effect of PRMT5 on vCyclin that facilitates cell cycle progression and proliferation, which provides a potential therapeutic target for KSHV-associated malignancies.
卡波西肉瘤相关疱疹病毒(KSHV)是一种双链 DNA 病毒,它编码许多细胞同源物,包括细胞周期蛋白 D、G 蛋白偶联蛋白、白细胞介素-6 以及巨噬细胞炎症蛋白 1 和 2。ORF72 编码的 KSHV vCyclin 是细胞周期蛋白 D2 的同源物。KSHV vCyclin 可通过组成性激活细胞周期蛋白依赖性激酶 6(CDK6)来调节病毒复制和细胞增殖。然而,KSHV vCyclin 的调控机制尚未完全阐明。在本研究中,我们发现了一种名为蛋白精氨酸甲基转移酶 5(PRMT5)的宿主蛋白能与 KSHV vCyclin 相互作用。我们进一步证实,PRMT5 通过转录激活被潜伏期相关核抗原(LANA)上调。值得注意的是,敲除或药物抑制(使用 EPZ015666)PRMT5 可抑制 KSHV 潜伏感染肿瘤细胞的细胞周期进展和细胞增殖。从机理上讲,PRMT5 在精氨酸 128 处对称地甲基化 vCyclin,并以依赖于甲基转移酶活性的方式稳定 vCyclin。我们还发现,PRMT5 对 vCyclin 的甲基化对磷酸化视网膜母细胞瘤蛋白(pRB)通路具有正向调节作用。总之,我们的研究结果揭示了 PRMT5 对 vCyclin 的重要调控作用,这种作用促进了细胞周期的进展和增殖,为 KSHV 相关恶性肿瘤提供了一个潜在的治疗靶点。
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引用次数: 0
The molecular determinants of a universal prion acceptor 通用朊病毒接受体的分子决定因素
IF 6.7 1区 医学 Q1 Immunology and Microbiology Pub Date : 2024-09-10 DOI: 10.1371/journal.ppat.1012538
Hamza Arshad, Zeel Patel, Zaid A. M. Al-Azzawi, Genki Amano, Leyao Li, Surabhi Mehra, Shehab Eid, Gerold Schmitt-Ulms, Joel C. Watts
In prion diseases, the species barrier limits the transmission of prions from one species to another. However, cross-species prion transmission is remarkably efficient in bank voles, and this phenomenon is mediated by the bank vole prion protein (BVPrP). The molecular determinants of BVPrP’s ability to function as a universal prion acceptor remain incompletely defined. Building on our finding that cultured cells expressing BVPrP can replicate both mouse and hamster prion strains, we systematically identified key residues in BVPrP that permit cross-species prion replication. We found that residues N155 and N170 of BVPrP, which are absent in mouse PrP but present in hamster PrP, are critical for cross-species prion replication. Additionally, BVPrP residues V112, I139, and M205, which are absent in hamster PrP but present in mouse PrP, are also required to enable replication of both mouse and hamster prions. Unexpectedly, we found that residues E227 and S230 near the C-terminus of BVPrP severely restrict prion accumulation following cross-species prion challenge, suggesting that they may have evolved to counteract the inherent propensity of BVPrP to misfold. PrP variants with an enhanced ability to replicate both mouse and hamster prions displayed accelerated spontaneous aggregation kinetics in vitro. These findings suggest that BVPrP’s unusual properties are governed by a key set of amino acids and that the enhanced misfolding propensity of BVPrP may enable cross-species prion replication.
在朊病毒疾病中,物种屏障限制了朊病毒从一个物种传播到另一个物种。然而,银行田鼠的跨物种朊病毒传播却非常有效,这种现象是由银行田鼠朊病毒蛋白(BVPrP)介导的。BVPrP 能够作为通用朊病毒接受者发挥作用的分子决定因素仍未完全明确。我们发现表达 BVPrP 的培养细胞可以复制小鼠和仓鼠朊病毒株,在此基础上,我们系统地鉴定了 BVPrP 中允许跨物种朊病毒复制的关键残基。我们发现,BVPrP 的 N155 和 N170 残基是跨物种朊病毒复制的关键,这两个残基在小鼠 PrP 中不存在,但在仓鼠 PrP 中存在。此外,在仓鼠 PrP 中不存在但在小鼠 PrP 中存在的 BVPrP 残基 V112、I139 和 M205 也是小鼠和仓鼠朊病毒复制所必需的。意想不到的是,我们发现 BVPrP C 端附近的残基 E227 和 S230 严重限制了跨物种朊病毒挑战后的朊病毒积累,这表明它们可能是为了抵消 BVPrP 本身的错误折叠倾向而进化而来的。复制小鼠和仓鼠朊病毒能力增强的 PrP 变体在体外显示出加速的自发聚集动力学。这些发现表明,BVPrP 的不寻常特性受一组关键氨基酸的支配,而 BVPrP 错误折叠倾向的增强可能使朊病毒得以跨物种复制。
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引用次数: 0
SDE19, a SEC-dependent effector from ‘Candidatus Liberibacter asiaticus’ suppresses plant immunity and targets Citrus sinensis Sec12 to interfere with vesicle trafficking SDE19是一种来自 "亚洲自由杆菌 "的依赖于SEC的效应子,可抑制植物免疫,并以柑橘Sec12为目标干扰囊泡贩运
IF 6.7 1区 医学 Q1 Immunology and Microbiology Pub Date : 2024-09-10 DOI: 10.1371/journal.ppat.1012542
Guiyan Huang, Xiaopeng Chang, Yanan Hu, Fuxuan Li, Nian Wang, Ruimin Li
Citrus huanglongbing (HLB), which is caused by the phloem-colonizing bacteria Candidatus Liberibacter asiaticus (CLas), poses a significant threat to citrus production worldwide. The pathogenicity mechanism of HLB remains poorly understood. SEC-dependent effectors (SDEs) have been suggested to play critical roles in the interaction between citrus and CLas. Here, we explored the function of CLIBASIA_05320 (SDE19), a core SDE from CLas, and its interaction with its host target. Our data revealed that SDE19 is expressed at higher level during infection of citrus than that during infection of the Asian citrus psyllid. Subcellular localization assays showed that SDE19 is localized in the nucleus and cytoplasm and is capable of moving from cell to cell in Nicotiana benthamiana. To investigate whether SDE19 facilitates pathogen infection, we generated transgenic Arabidopsis thaliana and citrus plants overexpressing SDE19. Transgenic A. thaliana and citrus plants were more susceptible to Pseudomonas syringae pv. tomato (Pst) and Xanthomonas citri subsp. citri (Xcc), respectively. In addition, RNA-seq analysis demonstrated that overexpression of SDE19 resulted in a reprogramming of expression of genes related to biotic stimulus responses. SDE19 interacts with Citrus sinensis Sec12, a guanine nucleotide exchange factor responsible for the assembly of plant COPII (coat protein II)-coated vesicles, which mediate vesicle trafficking from the ER to the Golgi. SDE19 colocalizes with Sec12 in the ER by binding to its N-terminal catalytic region, affecting the stability of Sec12 through the 26S proteasome. This interaction hinders the secretion of apoplastic defense-related proteins such as PR1, P69B, GmGIP1, and RCR3. Furthermore, the secretion of PR1 and callose deposition is decreased in SDE19-transgenic A. thaliana. Taken together, SDE19 is a novel virulent SDE secreted by CLas that interacts with Sec12 to disrupt vesicle trafficking, inhibit defense-related proteins secretion, and promote bacterial infection. This study sheds light on how CLas manipulates the host vesicle trafficking pathway to suppress the secretion of defense-related proteins and interfere with plant immunity.
柑橘黄龙病(HLB)是由韧皮部定殖细菌 Candidatus Liberibacter asiaticus(CLas)引起的,对全球柑橘生产构成严重威胁。人们对 HLB 的致病机制仍然知之甚少。有研究表明,SEC 依赖性效应器(SDEs)在柑橘与 CLas 的相互作用中发挥着关键作用。在此,我们探讨了 CLas 的核心 SDE CLIBASIA_05320(SDE19)的功能及其与宿主靶标的相互作用。我们的数据显示,SDE19在柑橘感染过程中的表达水平高于在亚洲柑橘虫害感染过程中的表达水平。亚细胞定位分析表明,SDE19定位于细胞核和细胞质中,并能在烟草中的细胞间移动。为了研究 SDE19 是否有助于病原体感染,我们生成了过表达 SDE19 的转基因拟南芥和柑橘植株。转基因拟南芥和柑橘植株分别对西红柿假单胞菌(Pst)和柠檬黄单胞菌亚种(Xcc)更敏感。此外,RNA-seq分析表明,SDE19的过表达导致与生物刺激反应相关的基因表达重编程。SDE19与Citrus sinensis Sec12相互作用,后者是一种鸟嘌呤核苷酸交换因子,负责组装植物COPII(衣壳蛋白II)包裹的囊泡,介导囊泡从ER向高尔基体的迁移。SDE19 通过与其 N 端催化区结合,在 ER 中与 Sec12 共定位,通过 26S 蛋白酶体影响 Sec12 的稳定性。这种相互作用阻碍了 PR1、P69B、GmGIP1 和 RCR3 等细胞凋亡防御相关蛋白的分泌。此外,在 SDE19 转基因的拟南芥中,PR1 的分泌和胼胝质的沉积都有所减少。综上所述,SDE19是一种由CLas分泌的新型毒性SDE,它能与Sec12相互作用,破坏囊泡贩运,抑制防御相关蛋白的分泌,促进细菌感染。这项研究揭示了CLas如何操纵宿主囊泡贩运途径,从而抑制防御相关蛋白的分泌,干扰植物免疫。
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引用次数: 0
Lactobacillus gasseri ATCC33323 affects the intestinal mucosal barrier to ameliorate DSS-induced colitis through the NR1I3-mediated regulation of E-cadherin 加塞乳杆菌 ATCC33323 通过 NR1I3 介导的 E-cadherin 调节作用影响肠粘膜屏障,从而改善 DSS 引起的结肠炎
IF 6.7 1区 医学 Q1 Immunology and Microbiology Pub Date : 2024-09-09 DOI: 10.1371/journal.ppat.1012541
Guanru Qian, Hui Zang, Jingtong Tang, Hao Zhang, Jiankang Yu, Huibiao Jia, Xinzhuang Zhang, Jianping Zhou
Inflammatory bowel disease (IBD) is an immune system disorder primarily characterized by colitis, the exact etiology of which remains unclear. Traditional treatment approaches currently yield limited efficacy and are associated with significant side effects. Extensive research has indicated the potent therapeutic effects of probiotics, particularly Lactobacillus strains, in managing colitis. However, the mechanisms through which Lactobacillus strains ameliorate colitis require further exploration. In our study, we selected Lactobacillus gasseri ATCC33323 from the intestinal microbiota to elucidate the specific mechanisms involved in modulation of colitis. Experimental findings in a DSS-induced colitis mouse model revealed that L. gasseri ATCC33323 significantly improved physiological damage in colitic mice, reduced the severity of colonic inflammation, decreased the production of inflammatory factors, and preserved the integrity of the intestinal epithelial structure and function. It also maintained the expression and localization of adhesive proteins while improving intestinal barrier permeability and restoring dysbiosis in the gut microbiota. E-cadherin, a critical adhesive protein, plays a pivotal role in this protective mechanism. Knocking down E-cadherin expression within the mouse intestinal tract significantly attenuated the ability of L. gasseri ATCC33323 to regulate colitis, thus confirming its protective role through E-cadherin. Finally, transcriptional analysis and in vitro experiments revealed that L. gasseri ATCC33323 regulates CDH1 transcription by affecting NR1I3, thereby promoting E-cadherin expression. These findings contribute to a better understanding of the specific mechanisms by which Lactobacillus strains alleviate colitis, offering new insights for the potential use of L. gasseri as an alternative therapy for IBD, particularly in dietary supplementation.
炎症性肠病(IBD)是一种以结肠炎为主要特征的免疫系统疾病,其确切病因尚不清楚。目前,传统的治疗方法疗效有限,而且副作用很大。大量研究表明,益生菌(尤其是乳酸杆菌菌株)在治疗结肠炎方面具有强大的疗效。然而,乳酸杆菌菌株改善结肠炎的机制还需要进一步探索。在我们的研究中,我们从肠道微生物群中选择了加塞乳杆菌(Lactobacillus gasseri ATCC33323),以阐明调节结肠炎的具体机制。在 DSS 诱导的结肠炎小鼠模型中的实验结果表明,L. gasseri ATCC33323 能显著改善结肠炎小鼠的生理损伤,降低结肠炎症的严重程度,减少炎症因子的产生,保持肠上皮结构和功能的完整性。它还能保持粘连蛋白的表达和定位,同时改善肠道屏障的通透性,恢复肠道微生物群的菌群失调。E-cadherin是一种重要的粘附蛋白,在这种保护机制中发挥着关键作用。在小鼠肠道内敲除 E-cadherin 的表达能显著削弱 L. gasseri ATCC33323 调节结肠炎的能力,从而证实了它通过 E-cadherin 发挥的保护作用。最后,转录分析和体外实验显示,L. gasseri ATCC33323 通过影响 NR1I3 来调节 CDH1 的转录,从而促进 E-cadherin 的表达。这些发现有助于更好地了解乳酸杆菌菌株缓解结肠炎的具体机制,为将 L. gasseri 用作 IBD 的替代疗法(尤其是膳食补充剂)提供了新的见解。
{"title":"Lactobacillus gasseri ATCC33323 affects the intestinal mucosal barrier to ameliorate DSS-induced colitis through the NR1I3-mediated regulation of E-cadherin","authors":"Guanru Qian, Hui Zang, Jingtong Tang, Hao Zhang, Jiankang Yu, Huibiao Jia, Xinzhuang Zhang, Jianping Zhou","doi":"10.1371/journal.ppat.1012541","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012541","url":null,"abstract":"Inflammatory bowel disease (IBD) is an immune system disorder primarily characterized by colitis, the exact etiology of which remains unclear. Traditional treatment approaches currently yield limited efficacy and are associated with significant side effects. Extensive research has indicated the potent therapeutic effects of probiotics, particularly <jats:italic>Lactobacillus</jats:italic> strains, in managing colitis. However, the mechanisms through which <jats:italic>Lactobacillus</jats:italic> strains ameliorate colitis require further exploration. In our study, we selected <jats:italic>Lactobacillus gasseri</jats:italic> ATCC33323 from the intestinal microbiota to elucidate the specific mechanisms involved in modulation of colitis. Experimental findings in a DSS-induced colitis mouse model revealed that <jats:italic>L</jats:italic>. <jats:italic>gasseri</jats:italic> ATCC33323 significantly improved physiological damage in colitic mice, reduced the severity of colonic inflammation, decreased the production of inflammatory factors, and preserved the integrity of the intestinal epithelial structure and function. It also maintained the expression and localization of adhesive proteins while improving intestinal barrier permeability and restoring dysbiosis in the gut microbiota. E-cadherin, a critical adhesive protein, plays a pivotal role in this protective mechanism. Knocking down E-cadherin expression within the mouse intestinal tract significantly attenuated the ability of <jats:italic>L</jats:italic>. <jats:italic>gasseri</jats:italic> ATCC33323 to regulate colitis, thus confirming its protective role through E-cadherin. Finally, transcriptional analysis and <jats:italic>in vitro</jats:italic> experiments revealed that <jats:italic>L</jats:italic>. <jats:italic>gasseri</jats:italic> ATCC33323 regulates <jats:italic>CDH1</jats:italic> transcription by affecting NR1I3, thereby promoting E-cadherin expression. These findings contribute to a better understanding of the specific mechanisms by which <jats:italic>Lactobacillus</jats:italic> strains alleviate colitis, offering new insights for the potential use of <jats:italic>L</jats:italic>. <jats:italic>gasseri</jats:italic> as an alternative therapy for IBD, particularly in dietary supplementation.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"7 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Immunization of cows with HIV envelope trimers generates broadly neutralizing antibodies to the V2-apex from the ultralong CDRH3 repertoire 用艾滋病毒包膜三聚体免疫奶牛,可产生针对超长 CDRH3 复合物中 V2-apex 的广泛中和抗体
IF 6.7 1区 医学 Q1 Immunology and Microbiology Pub Date : 2024-09-09 DOI: 10.1371/journal.ppat.1012042
Pilar X. Altman, Gabriel Ozorowski, Robyn L. Stanfield, Jeremy Haakenson, Michael Appel, Mara Parren, Wen-Hsin Lee, Huldah Sang, Jordan Woehl, Karen Saye-Francisco, Leigh M. Sewall, Collin Joyce, Ge Song, Katelyn Porter, Elise Landais, Raiees Andrabi, Ian A. Wilson, Andrew B. Ward, Waithaka Mwangi, Vaughn V. Smider, Dennis R. Burton, Devin Sok
The generation of broadly neutralizing antibodies (bnAbs) to conserved epitopes on HIV Envelope (Env) is one of the cornerstones of HIV vaccine research. The animal models commonly used for HIV do not reliably produce a potent broadly neutralizing serum antibody response, with the exception of cows. Cows have previously produced a CD4 binding site response by homologous prime and boosting with a native-like Env trimer. In small animal models, other engineered immunogens were shown to focus antibody responses to the bnAb V2-apex region of Env. Here, we immunized two groups of cows (n = 4) with two regimens of V2-apex focusing Env immunogens to investigate whether antibody responses could be generated to the V2-apex on Env. Group 1 was immunized with chimpanzee simian immunodeficiency virus (SIV)-Env trimer that shares its V2-apex with HIV, followed by immunization with C108, a V2-apex focusing immunogen, and finally boosted with a cross-clade native-like trimer cocktail. Group 2 was immunized with HIV C108 Env trimer followed by the same HIV trimer cocktail as Group 1. Longitudinal serum analysis showed that one cow in each group developed serum neutralizing antibody responses to the V2-apex. Eight and 11 bnAbs were isolated from Group 1 and Group 2 cows, respectively, and showed moderate breadth and potency. Potent and broad responses in this study developed much later than previous cow immunizations that elicited CD4bs bnAbs responses and required several different immunogens. All isolated bnAbs were derived from the ultralong CDRH3 repertoire. The finding that cow antibodies can target more than one broadly neutralizing epitope on the HIV surface reveals the generality of elongated structures for the recognition of highly glycosylated proteins. The exclusive isolation of ultralong CDRH3 bnAbs, despite only comprising a small percent of the cow repertoire, suggests these antibodies outcompete the long and short CDRH3 antibodies during the bnAb response.
针对 HIV 包膜(Env)上的保守表位产生广泛中和抗体(bnAbs)是 HIV 疫苗研究的基石之一。常用的 HIV 动物模型不能可靠地产生有效的广谱中和血清抗体反应,但奶牛除外。以前,奶牛曾通过同源质粒和类本地 Env 三聚体增强产生 CD4 结合位点反应。在小动物模型中,其他工程免疫原被证明能使抗体反应集中到 Env 的 bnAb V2-apex 区域。在这里,我们用两种V2-apex集中Env免疫原免疫两组奶牛(n = 4),以研究是否能产生针对Env上V2-apex的抗体反应。第 1 组使用黑猩猩猿猴免疫缺陷病毒(SIV)-Env 三聚体(与 HIV 共享 V2-apex)进行免疫,然后使用 C108(V2-apex 聚焦免疫原)进行免疫,最后使用交叉支链本地样三聚体鸡尾酒进行强化。纵向血清分析表明,每组中都有一头牛产生了针对 V2-apex 的血清中和抗体反应。从第 1 组和第 2 组奶牛中分别分离出 8 种和 11 种 bnAbs,并显示出适度的广泛性和效力。这项研究中的强效和广泛反应比以前的奶牛免疫晚得多,以前的奶牛免疫会引起 CD4bs bnAbs 反应,而且需要几种不同的免疫原。所有分离出的 bnAbs 都来自超长 CDRH3 序列。奶牛抗体可以针对 HIV 表面一个以上的广谱中和表位,这一发现揭示了细长结构在识别高度糖基化蛋白质方面的普遍性。尽管超长 CDRH3 bnAbs 只占奶牛抗体库的一小部分,但它们的独家分离结果表明,在 bnAb 反应过程中,这些抗体会取代长 CDRH3 和短 CDRH3 抗体。
{"title":"Immunization of cows with HIV envelope trimers generates broadly neutralizing antibodies to the V2-apex from the ultralong CDRH3 repertoire","authors":"Pilar X. Altman, Gabriel Ozorowski, Robyn L. Stanfield, Jeremy Haakenson, Michael Appel, Mara Parren, Wen-Hsin Lee, Huldah Sang, Jordan Woehl, Karen Saye-Francisco, Leigh M. Sewall, Collin Joyce, Ge Song, Katelyn Porter, Elise Landais, Raiees Andrabi, Ian A. Wilson, Andrew B. Ward, Waithaka Mwangi, Vaughn V. Smider, Dennis R. Burton, Devin Sok","doi":"10.1371/journal.ppat.1012042","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012042","url":null,"abstract":"The generation of broadly neutralizing antibodies (bnAbs) to conserved epitopes on HIV Envelope (Env) is one of the cornerstones of HIV vaccine research. The animal models commonly used for HIV do not reliably produce a potent broadly neutralizing serum antibody response, with the exception of cows. Cows have previously produced a CD4 binding site response by homologous prime and boosting with a native-like Env trimer. In small animal models, other engineered immunogens were shown to focus antibody responses to the bnAb V2-apex region of Env. Here, we immunized two groups of cows (n = 4) with two regimens of V2-apex focusing Env immunogens to investigate whether antibody responses could be generated to the V2-apex on Env. Group 1 was immunized with chimpanzee simian immunodeficiency virus (SIV)-Env trimer that shares its V2-apex with HIV, followed by immunization with C108, a V2-apex focusing immunogen, and finally boosted with a cross-clade native-like trimer cocktail. Group 2 was immunized with HIV C108 Env trimer followed by the same HIV trimer cocktail as Group 1. Longitudinal serum analysis showed that one cow in each group developed serum neutralizing antibody responses to the V2-apex. Eight and 11 bnAbs were isolated from Group 1 and Group 2 cows, respectively, and showed moderate breadth and potency. Potent and broad responses in this study developed much later than previous cow immunizations that elicited CD4bs bnAbs responses and required several different immunogens. All isolated bnAbs were derived from the ultralong CDRH3 repertoire. The finding that cow antibodies can target more than one broadly neutralizing epitope on the HIV surface reveals the generality of elongated structures for the recognition of highly glycosylated proteins. The exclusive isolation of ultralong CDRH3 bnAbs, despite only comprising a small percent of the cow repertoire, suggests these antibodies outcompete the long and short CDRH3 antibodies during the bnAb response.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"185 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Oxaloacetate anaplerosis differently contributes to pathogenicity in plant pathogenic fungi Fusarium graminearum and F. oxysporum 草酰乙酸无性繁殖对植物病原真菌禾本科镰刀菌和草孢菌致病性的不同贡献
IF 6.7 1区 医学 Q1 Immunology and Microbiology Pub Date : 2024-09-09 DOI: 10.1371/journal.ppat.1012544
Soobin Shin, Seonghun Bong, Heeji Moon, Hosung Jeon, Hun Kim, Gyung Ja Choi, Do Yup Lee, Hokyoung Son
Anaplerosis refers to enzymatic reactions or pathways replenishing metabolic intermediates in the tricarboxylic acid (TCA) cycle. Pyruvate carboxylase (PYC) plays an important anaplerotic role by catalyzing pyruvate carboxylation, forming oxaloacetate. Although PYC orthologs are well conserved in prokaryotes and eukaryotes, their pathobiological functions in filamentous pathogenic fungi have yet to be fully understood. Here, we delve into the molecular functions of the ortholog gene PYC1 in Fusarium graminearum and F. oxysporum, prominent fungal plant pathogens with distinct pathosystems, demonstrating variations in carbon metabolism for pathogenesis. Surprisingly, the PYC1 deletion mutant of F. oxysporum exhibited pleiotropic defects in hyphal growth, conidiation, and virulence, unlike F. graminearum, where PYC1 deletion did not significantly impact virulence. To further explore the species-specific effects of PYC1 deletion on pathogenicity, we conducted comprehensive metabolic profiling. Despite shared metabolic changes, distinct reprogramming in central carbon and nitrogen metabolism was identified. Specifically, alpha-ketoglutarate, a key link between the TCA cycle and amino acid metabolism, showed significant down-regulation exclusively in the PYC1 deletion mutant of F. oxysporum. The metabolic response associated with pathogenicity was notably characterized by S-methyl-5-thioadenosine and S-adenosyl-L-methionine. This research sheds light on how PYC1-mediated anaplerosis affects fungal metabolism and reveals species-specific variations, exemplified in F. graminearum and F. oxysporum.
无氧代谢是指补充三羧酸(TCA)循环中代谢中间产物的酶促反应或途径。丙酮酸羧化酶(PYC)通过催化丙酮酸羧化形成草酰乙酸,发挥着重要的无功补偿作用。虽然PYC的同源物在原核生物和真核生物中十分保守,但它们在丝状致病真菌中的病理生物学功能尚未完全清楚。在这里,我们深入研究了禾谷镰刀菌(Fusarium graminearum)和氧孢镰刀菌(F. oxysporum)中PYC1直向同源基因的分子功能。令人惊讶的是,氧孢镰刀菌的PYC1缺失突变体在头状花序生长、分生孢子和毒力方面表现出多效应缺陷,而禾谷镰刀菌则不同,其PYC1缺失对毒力没有显著影响。为了进一步探索PYC1缺失对致病性的物种特异性影响,我们进行了全面的代谢分析。尽管发生了共同的代谢变化,但在中心碳和氮代谢中发现了不同的重编程。具体来说,作为 TCA 循环和氨基酸代谢之间的关键环节,α-酮戊二酸仅在 F. oxysporum 的PYC1 基因缺失突变体中出现了显著的下调。与致病性相关的代谢反应主要以 S-甲基-5-硫代腺苷和 S-腺苷-L-蛋氨酸为特征。这项研究揭示了PYC1介导的无丝分裂如何影响真菌代谢,并揭示了禾谷镰刀菌和草孢镰刀菌的物种特异性差异。
{"title":"Oxaloacetate anaplerosis differently contributes to pathogenicity in plant pathogenic fungi Fusarium graminearum and F. oxysporum","authors":"Soobin Shin, Seonghun Bong, Heeji Moon, Hosung Jeon, Hun Kim, Gyung Ja Choi, Do Yup Lee, Hokyoung Son","doi":"10.1371/journal.ppat.1012544","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012544","url":null,"abstract":"Anaplerosis refers to enzymatic reactions or pathways replenishing metabolic intermediates in the tricarboxylic acid (TCA) cycle. Pyruvate carboxylase (PYC) plays an important anaplerotic role by catalyzing pyruvate carboxylation, forming oxaloacetate. Although PYC orthologs are well conserved in prokaryotes and eukaryotes, their pathobiological functions in filamentous pathogenic fungi have yet to be fully understood. Here, we delve into the molecular functions of the ortholog gene <jats:italic>PYC1</jats:italic> in <jats:italic>Fusarium graminearum</jats:italic> and <jats:italic>F</jats:italic>. <jats:italic>oxysporum</jats:italic>, prominent fungal plant pathogens with distinct pathosystems, demonstrating variations in carbon metabolism for pathogenesis. Surprisingly, the <jats:italic>PYC1</jats:italic> deletion mutant of <jats:italic>F</jats:italic>. <jats:italic>oxysporum</jats:italic> exhibited pleiotropic defects in hyphal growth, conidiation, and virulence, unlike <jats:italic>F</jats:italic>. <jats:italic>graminearum</jats:italic>, where <jats:italic>PYC1</jats:italic> deletion did not significantly impact virulence. To further explore the species-specific effects of <jats:italic>PYC1</jats:italic> deletion on pathogenicity, we conducted comprehensive metabolic profiling. Despite shared metabolic changes, distinct reprogramming in central carbon and nitrogen metabolism was identified. Specifically, alpha-ketoglutarate, a key link between the TCA cycle and amino acid metabolism, showed significant down-regulation exclusively in the <jats:italic>PYC1</jats:italic> deletion mutant of <jats:italic>F</jats:italic>. <jats:italic>oxysporum</jats:italic>. The metabolic response associated with pathogenicity was notably characterized by S-methyl-5-thioadenosine and S-adenosyl-L-methionine. This research sheds light on how <jats:italic>PYC1</jats:italic>-mediated anaplerosis affects fungal metabolism and reveals species-specific variations, exemplified in <jats:italic>F</jats:italic>. <jats:italic>graminearum</jats:italic> and <jats:italic>F</jats:italic>. <jats:italic>oxysporum</jats:italic>.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"14 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Evolutionary dynamics in gut-colonizing Candida glabrata during caspofungin therapy: Emergence of clinically important mutations in sphingolipid biosynthesis 在卡泊芬净治疗期间,肠道定植念珠菌的进化动态:鞘脂生物合成中出现具有临床意义的突变
IF 6.7 1区 医学 Q1 Immunology and Microbiology Pub Date : 2024-09-09 DOI: 10.1371/journal.ppat.1012521
Yasmine Hassoun, Ariel A. Aptekmann, Mikhail V. Keniya, Rosa Y. Gomez, Nicole Alayo, Giovanna Novi, Christopher Quinteros, Firat Kaya, Matthew Zimmerman, Diego H. Caceres, Nancy A. Chow, David S. Perlin, Erika Shor
Invasive fungal infections are associated with high mortality, which is exacerbated by the limited antifungal drug armamentarium and increasing antifungal drug resistance. Echinocandins are a frontline antifungal drug class targeting β-glucan synthase (GS), a fungal cell wall biosynthetic enzyme. Echinocandin resistance is generally low but increasing in species like Candida glabrata, an opportunistic yeast pathogen colonizing human mucosal surfaces. Mutations in GS-encoding genes (FKS1 and FKS2 in C. glabrata) are strongly associated with clinical echinocandin failure, but epidemiological studies show that other, as yet unidentified factors also influence echinocandin susceptibility. Furthermore, although the gut is known to be an important reservoir for emergence of drug-resistant strains, the evolution of resistance is not well understood. Here, we studied the evolutionary dynamics of C. glabrata colonizing the gut of immunocompetent mice during treatment with caspofungin, a widely-used echinocandin. Whole genome and amplicon sequencing revealed rapid genetic diversification of this C. glabrata population during treatment and the emergence of both drug target (FKS2) and non-drug target mutations, the latter predominantly in the FEN1 gene encoding a fatty acid elongase functioning in sphingolipid biosynthesis. The fen1 mutants displayed high fitness in the gut specifically during caspofungin treatment and contained high levels of phytosphingosine, whereas genetic depletion of phytosphingosine by deletion of YPC1 gene hypersensitized the wild type strain to caspofungin and was epistatic to fen1Δ. Furthermore, high resolution imaging and mass spectrometry showed that reduced caspofungin susceptibility in fen1Δ cells was associated with reduced caspofungin binding to the plasma membrane. Finally, we identified several different fen1 mutations in clinical C. glabrata isolates, which phenocopied the fen1Δ mutant, causing reduced caspofungin susceptibility. These studies reveal new genetic and molecular determinants of clinical caspofungin susceptibility and illuminate the dynamic evolution of drug target and non-drug target mutations reducing echinocandin efficacy in patients colonized with C. glabrata.
侵袭性真菌感染死亡率很高,而抗真菌药物种类有限和抗真菌药物耐药性不断增加又加剧了这一问题。棘白菌素类是以真菌细胞壁生物合成酶β-葡聚糖合成酶(GS)为靶点的一线抗真菌药物。棘白菌素类药物的耐药性一般较低,但在一些菌种(如定植于人体粘膜表面的机会性酵母病原体--光滑念珠菌)中的耐药性却在不断增加。GS编码基因(C. glabrata中的FKS1和FKS2)的突变与临床棘白菌素失效密切相关,但流行病学研究表明,其他尚未确定的因素也会影响对棘白菌素的敏感性。此外,虽然已知肠道是耐药菌株出现的重要贮藏库,但对耐药性的进化却不甚了解。在此,我们研究了免疫功能正常的小鼠在接受卡泊芬净(一种广泛使用的棘白菌素)治疗期间,其肠道中胶孢子菌的进化动态。全基因组和扩增片段测序显示,在治疗过程中,草履虫群体的基因迅速多样化,并出现了药物靶标(FKS2)和非药物靶标突变,后者主要出现在编码脂肪酸伸长酶的 FEN1 基因中,该基因在鞘脂生物合成中起作用。在卡泊芬净处理期间,fen1突变体在肠道中表现出较高的适应性,并含有较高水平的植物鞘磷脂,而通过删除YPC1基因对植物鞘磷脂进行遗传耗竭,可使野生型菌株对卡泊芬净过敏,并与fen1Δ具有表观关系。此外,高分辨率成像和质谱分析表明,fen1Δ细胞对卡泊芬净的敏感性降低与卡泊芬净与质膜的结合减少有关。最后,我们在临床上发现了几种不同的fen1突变,它们与fen1Δ突变体表型相同,导致对卡泊芬净的敏感性降低。这些研究揭示了临床上对卡泊芬净敏感性的新的遗传和分子决定因素,并阐明了药物靶标和非药物靶标突变的动态演化,这些突变降低了定植有青霉藻患者的棘球蚴素疗效。
{"title":"Evolutionary dynamics in gut-colonizing Candida glabrata during caspofungin therapy: Emergence of clinically important mutations in sphingolipid biosynthesis","authors":"Yasmine Hassoun, Ariel A. Aptekmann, Mikhail V. Keniya, Rosa Y. Gomez, Nicole Alayo, Giovanna Novi, Christopher Quinteros, Firat Kaya, Matthew Zimmerman, Diego H. Caceres, Nancy A. Chow, David S. Perlin, Erika Shor","doi":"10.1371/journal.ppat.1012521","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012521","url":null,"abstract":"Invasive fungal infections are associated with high mortality, which is exacerbated by the limited antifungal drug armamentarium and increasing antifungal drug resistance. Echinocandins are a frontline antifungal drug class targeting β-glucan synthase (GS), a fungal cell wall biosynthetic enzyme. Echinocandin resistance is generally low but increasing in species like <jats:italic>Candida glabrata</jats:italic>, an opportunistic yeast pathogen colonizing human mucosal surfaces. Mutations in GS-encoding genes (<jats:italic>FKS1</jats:italic> and <jats:italic>FKS2</jats:italic> in <jats:italic>C</jats:italic>. <jats:italic>glabrata</jats:italic>) are strongly associated with clinical echinocandin failure, but epidemiological studies show that other, as yet unidentified factors also influence echinocandin susceptibility. Furthermore, although the gut is known to be an important reservoir for emergence of drug-resistant strains, the evolution of resistance is not well understood. Here, we studied the evolutionary dynamics of <jats:italic>C</jats:italic>. <jats:italic>glabrata</jats:italic> colonizing the gut of immunocompetent mice during treatment with caspofungin, a widely-used echinocandin. Whole genome and amplicon sequencing revealed rapid genetic diversification of this <jats:italic>C</jats:italic>. <jats:italic>glabrata</jats:italic> population during treatment and the emergence of both drug target (<jats:italic>FKS2</jats:italic>) and non-drug target mutations, the latter predominantly in the <jats:italic>FEN1</jats:italic> gene encoding a fatty acid elongase functioning in sphingolipid biosynthesis. The <jats:italic>fen1</jats:italic> mutants displayed high fitness in the gut specifically during caspofungin treatment and contained high levels of phytosphingosine, whereas genetic depletion of phytosphingosine by deletion of <jats:italic>YPC1</jats:italic> gene hypersensitized the wild type strain to caspofungin and was epistatic to <jats:italic>fen1Δ</jats:italic>. Furthermore, high resolution imaging and mass spectrometry showed that reduced caspofungin susceptibility in <jats:italic>fen1Δ</jats:italic> cells was associated with reduced caspofungin binding to the plasma membrane. Finally, we identified several different <jats:italic>fen1</jats:italic> mutations in clinical <jats:italic>C</jats:italic>. <jats:italic>glabrata</jats:italic> isolates, which phenocopied the <jats:italic>fen1Δ</jats:italic> mutant, causing reduced caspofungin susceptibility. These studies reveal new genetic and molecular determinants of clinical caspofungin susceptibility and illuminate the dynamic evolution of drug target and non-drug target mutations reducing echinocandin efficacy in patients colonized with <jats:italic>C</jats:italic>. <jats:italic>glabrata</jats:italic>.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":"105 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multi-omics analysis of SIV-specific CD8+ T cells in multiple anatomical sites 对多个解剖部位的 SIV 特异性 CD8+ T 细胞进行多组学分析
IF 6.7 1区 医学 Q1 Immunology and Microbiology Pub Date : 2024-09-09 DOI: 10.1371/journal.ppat.1012545
Jennifer Simpson, Brittany Dulek, Paul Schaughency, Jason M. Brenchley
CD8+ T cells exert immunological pressure against immunodeficiency lentiviruses. In previous studies, we examined the TCR repertoire of CD8+ T cells specific for a single SIV immunodominant epitope, Gag-CM9, throughout SIV infection or after vaccination, and across multiple anatomic sites. We identified both tissue specific TCR sequences and TCRs shared by multiple anatomical sites. Here we use single cell RNA sequencing to evaluate if the tissue localization or TCR sequence of a CM9-specific CD8+ T cell corresponds with unique transcriptomics. CM9-specific CD8+ T cells were sorted from blood, lymph nodes, spleen, and liver from SIV infected rhesus macaques with progressive SIV infection and in animals who spontaneously control SIV replication after cessation of antiretroviral therapy. The cells were processed through a single cell sequencing protocol, creating a TCR amplified library and an RNA gene expression library corresponding to individual cells. Gene set enrichment analysis revealed no distinct transcriptional profiles for CM9 specific CD8+ T cells between different anatomical sites and between cells with shared or tissue specific TCRs. Similarly, no clear transcriptional profiles were associated with clonotypes which were shared across individual animals. However, CM9 specific CD8+ T cells from posttreatment controllers did exhibit enrichment of pathways associated with cellular activation compared to progressively infected animals, suggesting that altered transcription in distinct cellular pathways in antigen specific CD8+ T cells may associate with viral control. Together, these studies represent a thorough analysis of the relationship between anatomical and clonal origin, and the transcriptional profile of antigen specific CD8+ T cells and unravel pathways that may be important for CD8+ T cell mediated control of SIV replication.
CD8+ T细胞对免疫缺陷慢病毒产生免疫压力。在之前的研究中,我们研究了在整个 SIV 感染过程中或接种疫苗后,CD8+ T 细胞对单一 SIV 免疫优势表位(Gag-CM9)特异性的 TCR 反应谱,以及跨多个解剖部位的 TCR 反应谱。我们发现了组织特异性 TCR 序列和多个解剖部位共有的 TCR。在此,我们使用单细胞 RNA 测序来评估 CM9 特异性 CD8+ T 细胞的组织定位或 TCR 序列是否与独特的转录组学相对应。我们从SIV感染猕猴的血液、淋巴结、脾脏和肝脏中分拣出了CM9特异性CD8+ T细胞,这些猕猴患有进行性SIV感染,而且在停止抗逆转录病毒治疗后自发控制了SIV复制。这些细胞通过单细胞测序方案进行处理,建立了与单个细胞相对应的 TCR 扩增文库和 RNA 基因表达文库。基因组富集分析显示,CM9 特异性 CD8+ T 细胞在不同解剖部位之间、具有共享或组织特异性 TCR 的细胞之间没有明显的转录特征。同样,动物个体间共享的克隆型也没有明显的转录特征。不过,与渐进感染的动物相比,治疗后控制者的 CM9 特异性 CD8+ T 细胞确实表现出与细胞活化相关的通路富集,这表明抗原特异性 CD8+ T 细胞中不同细胞通路的转录改变可能与病毒控制有关。总之,这些研究全面分析了解剖和克隆起源与抗原特异性 CD8+ T 细胞转录特征之间的关系,并揭示了可能对 CD8+ T 细胞介导的 SIV 复制控制很重要的途径。
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引用次数: 0
NLRP1-dependent activation of Gasdermin D in neutrophils controls cutaneous leishmaniasis 中性粒细胞中依赖 NLRP1 激活的 Gasdermin D 可控制皮肤利什曼病
IF 6.7 1区 医学 Q1 Immunology and Microbiology Pub Date : 2024-09-09 DOI: 10.1371/journal.ppat.1012527
Michiel Goris, Katiuska Passelli, Sanam Peyvandi, Miriam Díaz-Varela, Oaklyne Billion, Borja Prat-Luri, Benjamin Demarco, Chantal Desponds, Manon Termote, Eva Iniguez, Somaditya Dey, Bernard Malissen, Shaden Kamhawi, Benjamin P. Hurrell, Petr Broz, Fabienne Tacchini-Cottier
Intracellular pathogens that replicate in host myeloid cells have devised ways to inhibit the cell’s killing machinery. Pyroptosis is one of the host strategies used to reduce the pathogen replicating niche and thereby control its expansion. The intracellular Leishmania parasites can survive and use neutrophils as a silent entry niche, favoring subsequent parasite dissemination into the host. Here, we show that Leishmania mexicana induces NLRP1- and caspase-1-dependent Gasdermin D (GSDMD)-mediated pyroptosis in neutrophils, a process critical to control the parasite-induced pathology. In the absence of GSDMD, we observe an increased number of infected dermal neutrophils two days post-infection. Using adoptive neutrophil transfer in neutropenic mice, we show that pyroptosis contributes to the regulation of the neutrophil niche early after infection. The critical role of neutrophil pyroptosis and its positive influence on the regulation of the disease outcome was further demonstrated following infection of mice with neutrophil-specific deletion of GSDMD. Thus, our study establishes neutrophil pyroptosis as a critical regulator of leishmaniasis pathology.
在宿主骨髓细胞中复制的细胞内病原体已经设计出了抑制细胞杀伤机制的方法。嗜热细胞增多症是宿主用来减少病原体复制生态位从而控制其扩张的策略之一。细胞内的利什曼原虫可以存活下来,并利用中性粒细胞作为无声的进入龛位,有利于寄生虫随后传播到宿主体内。在这里,我们发现墨西哥利什曼原虫会诱导中性粒细胞发生依赖 NLRP1 和 Caspase-1 的 Gasdermin D(GSDMD)介导的热凋亡,这一过程对于控制寄生虫诱导的病理变化至关重要。在 GSDMD 缺失的情况下,我们观察到感染后两天受感染的真皮中性粒细胞数量增加。通过在中性粒细胞嗜中性小鼠中进行收养性中性粒细胞转移,我们发现嗜中性粒细胞热解有助于在感染后早期调节中性粒细胞生态位。在中性粒细胞特异性缺失 GSDMD 的小鼠感染后,我们进一步证实了中性粒细胞热解的关键作用及其对疾病结局调节的积极影响。因此,我们的研究确定了中性粒细胞的嗜热性是利什曼病病理学的一个关键调节因子。
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引用次数: 0
Trem2/Syk/PI3K axis contributes to the host protection against Toxoplasma gondii-induced adverse pregnancy outcomes via modulating decidual macrophages Trem2/Syk/PI3K轴通过调节蜕膜巨噬细胞,帮助宿主抵御弓形虫诱发的不良妊娠结局
IF 6.7 1区 医学 Q1 Immunology and Microbiology Pub Date : 2024-09-09 DOI: 10.1371/journal.ppat.1012543
Qing Wang, Yining Cao, Songyi Ye, Maoyuan Ding, Wenliang Ge, Yuejin Liang, Jinling Chen
Decidual macrophages residing at the maternal-fetal interface have been recognized as pivotal factors for maintaining normal pregnancy; however, they are also key target cells of Toxoplasma gondii (T. gondii) in the pathology of T. gondii-induced adverse pregnancy. Trem2, as a functional receptor on macrophage surface, recognizes and binds various kinds of pathogens. The role and underlying mechanism of Trem2 in T. gondii infection remain elusive. In the present study, we found that T. gondii infection downregulated Trem2 expression and that Trem2-/- mice exhibited more severe adverse pregnancy outcomes than wildtype mice. We also demonstrated that T. gondii infection resulted in increased decidual macrophages, which were significantly reduced in the Trem2-/- pregnant mouse model as compared to wildtype control animals. We further described the inhibited proliferation, migration, and invasion functions of trophoblast cell by T. gondii antigens through macrophages as an "intermediate bridge", while this inhibition can be rescued by Trem2 agonist HSP60. Concurrently, Trem2 deficiency in bone marrow-derived macrophages (BMDMs) heightened the inhibitory effect of TgAg on the migration and invasion of trophoblast cells, accompanied by higher pro-inflammatory factors (IL-1β, IL-6 and TNF-α) but a lower chemokine (CXCL1) in T. gondii antigens-treated BMDMs. Furthermore, compelling evidence from animal models and in vitro cell experiments suggests that T. gondii inhibits the Trem2-Syk-PI3K signaling pathway, leading to impaired function of decidual macrophages. Therefore, our findings highlight Trem2 signaling as an essential pathway by which decidual macrophages respond to T. gondii infection, suggesting Trem2 as a crucial sensor of decidual macrophages and potential therapeutic target in the pathology of T. gondii-induced adverse pregnancy.
驻留在母胎界面的蜕膜巨噬细胞被认为是维持正常妊娠的关键因素,但它们也是弓形虫(T. gondii)在T. gondii引起的不良妊娠病理学中的关键靶细胞。Trem2 作为巨噬细胞表面的功能性受体,可识别并结合各种病原体。Trem2在淋病双球菌感染中的作用及其内在机制仍未确定。在本研究中,我们发现淋球菌感染会下调Trem2的表达,Trem2-/-小鼠比野生型小鼠表现出更严重的不良妊娠结局。我们还证实,淋球菌感染导致蜕膜巨噬细胞增加,与野生型对照组相比,Trem2-/-妊娠小鼠模型中的巨噬细胞显著减少。我们进一步描述了淋球菌抗原通过巨噬细胞这一 "中间桥梁 "对滋养层细胞增殖、迁移和侵袭功能的抑制作用,而这种抑制作用可被Trem2激动剂HSP60所挽救。同时,骨髓源性巨噬细胞(BMDMs)缺乏Trem2会增强TgAg对滋养层细胞迁移和侵袭的抑制作用,同时T.gondii抗原处理的BMDMs中的促炎因子(IL-1β、IL-6和TNF-α)较高,而趋化因子(CXCL1)较低。此外,来自动物模型和体外细胞实验的有力证据表明,淋球菌抑制了Trem2-Syk-PI3K信号通路,导致蜕膜巨噬细胞功能受损。因此,我们的研究结果突显了Trem2信号传导是蜕膜巨噬细胞对淋病双球菌感染做出反应的重要途径,这表明Trem2是蜕膜巨噬细胞的一个关键传感器,也是淋病双球菌诱导的不良妊娠病理学的潜在治疗靶点。
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