Microbes and Infection最新文献_第9页

Phylogenetic analysis of Mycobacterium caprae highlights past and present epidemiological links at the Iberian Peninsula scale Caprae 分枝杆菌的系统发育分析凸显了伊比利亚半岛过去和现在的流行病学联系。

IF 2.6 4区医学 Q3 IMMUNOLOGY

Microbes and Infection

Pub Date : 2025-02-01 DOI: 10.1016/j.micinf.2024.105405

André C. Pereira , Bernat Pérez de Val , Mónica V. Cunha

Mycobacterium caprae is linked to regular outbreaks of tuberculosis (TB) in geographically distinct caprine populations across Europe, namely Iberia where this ecovar may represent up to 8% of total animal TB cases, circulating in multi-host communities encompassing domestic ruminants and wildlife, representing severe financial losses. It also causes zoonotic human disease. In this work, we undertake the first phylodynamic and phylogeographic analyses of M. caprae to reconstruct past demography and transmission chains. First, we examined the worldwide diversity of M. caprae based on 229 unpublished and publicly available whole genome sequences, depicting Asian, Central-East European, and Iberian clades. Phylodynamic analyses of the SB0157 Iberian clade (n = 81) positioned the most recent common ancestor in goats, around 100 years ago. Host transition events were common between goats, wild boars, and humans, possibly resulting from mixed farming, extensive management, and close human proximity, facilitating interspecific transmission. We show the spread of M. caprae on multiple scales due to local and transnational animal trade, supporting historical and sustained cross-species transmission in Iberia. We highlight the value of intersecting genomic epidemiology with molecular ecology to resolve epidemiological links and show that an EU-official eradication program in goats is utterly needed to control TB in a multi-host scenario.

在欧洲，即伊比利亚，毛冠分枝杆菌与地理位置不同的毛冠种群中定期爆发的结核病（TB）有关，在伊比利亚，这种生态型分枝杆菌可能占动物结核病病例总数的 8%，在包括家养反刍动物和野生动物在内的多宿主群落中循环，造成严重的经济损失。它还会引起人畜共患病。在这项工作中，我们首次对 Caprae 真菌进行了系统动力学和系统地理学分析，以重建其过去的种群分布和传播链。首先，我们基于 229 个未发表和公开的全基因组序列，研究了胭脂虫在全球范围内的多样性，描绘了亚洲、中东欧和伊比利亚支系。SB0157伊比利亚支系（n=81）的系统动力学分析将最近的共同祖先定位于山羊，即大约 100 年前。在山羊、野猪和人类之间，宿主转换事件很常见，这可能是由于混合养殖、粗放管理和人类的接近，促进了种间传播。我们的研究表明，由于当地和跨国的动物贸易，胭脂虫在多个范围内传播，支持了伊比利亚历史上持续的跨物种传播。我们强调了基因组流行病学与分子生态学相互交叉以解决流行病学联系的价值，并表明欧盟完全有必要在山羊中实施官方根除计划，以控制多宿主情况下的结核病。

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引用次数: 0

The replacement of ergosterol with alternative sterols affects the physiological function of the yeast plasma membrane, including its H+-ATPase activity and resistance to antifungal drugs 用替代固醇取代麦角甾醇会影响酵母质膜的生理功能，包括其 H+-ATP 酶活性和对抗真菌药物的抗性。

IF 2.6 4区医学 Q3 IMMUNOLOGY

Microbes and Infection

Pub Date : 2025-02-01 DOI: 10.1016/j.micinf.2024.105409

Marie Kodedová , Martin Valachovič , Hana Sychrová

Sterols perform essential structural and signalling functions in living organisms. Ergosterol contributes to the fluidity, permeability, microdomain formation and functionality of proteins in the yeast membrane. In our study, desmosterol was the most successful at compensating for the lack of ergosterol in Saccharomyces cerevisiae, besides stigmasterol and sitosterol. These three sterols supported cell growth without causing severe morphological defects, unlike cholesterol, 7-dehydrocholesterol, lathosterol, cholestanol or lanosterol. Together with ergosterol, they were also able to bring the plasma membrane potential of hem1Δ cells closer to the level of the wild type. In addition, desmosterol conferred even higher thermotolerance to yeast than ergosterol. Some sterols counteracted the antifungal toxicity of polyenes, azoles and terbinafine to hem1Δ cells. Plant sterols (stigmasterol, sitosterol) and desmosterol ensured the glucose-induced activation of H⁺-ATPase in hem1Δ cells analogously to ergosterol, whereas cholesterol and 7-dehydrocholesterol were less effective. Exogenous ergosterol, stigmasterol, sitosterol, desmosterol and cholesterol also improved the growth of Candida glabrata and Candida albicans in the presence of inhibitory concentration of fluconazole. The proper incorporation of exogenous sterols into the membrane with minimal adverse side effects on membrane functions was mainly influenced by the structure of the sterol acyl chain, and less by their ring structures.

甾醇在生物体内发挥着重要的结构和信号功能。麦角甾醇有助于酵母膜的流动性、渗透性、微域的形成和蛋白质的功能。在我们的研究中，除麦角甾醇和谷甾醇外，去麦角甾醇最能成功地弥补麦角甾醇在酿酒酵母中的缺乏。与胆固醇、7-脱氢胆固醇、棉子甾醇、胆甾醇或羊毛甾醇不同，这三种甾醇在支持细胞生长的同时不会造成严重的形态缺陷。与麦角甾醇一起，它们还能使 hem1Δ 细胞的质膜电位更接近野生型的水平。此外，脱甾醇赋予酵母的耐热性甚至高于麦角甾醇。一些固醇可以抵消多烯类、唑类和特比萘芬对 hem1Δ 细胞的抗真菌毒性。植物甾醇（豆甾醇、西固醇）和脱甾醇可确保葡萄糖诱导的 H+-ATP 酶在 hem1Δ 细胞中的活化，其效果与麦角甾醇类似，而胆固醇和 7-脱氢胆固醇的效果较差。外源性麦角甾醇、豆甾醇、赤藓醇、脱脂甾醇和胆固醇也能在氟康唑抑制浓度存在的情况下改善草履虫和白僵菌的生长。外源固醇能否在对膜功能产生最小副作用的情况下适当地融入膜中，主要受固醇酰基链结构的影响，而受其环状结构的影响较小。

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引用次数: 0

High-resolution kinetics and cellular determinants of SARS-CoV-2 antibody response over two years after COVID-19 vaccination 接种 COVID-19 疫苗两年后，SARS-CoV-2 抗体反应的高分辨率动力学和细胞决定因素。

IF 2.6 4区医学 Q3 IMMUNOLOGY

Microbes and Infection

Pub Date : 2025-02-01 DOI: 10.1016/j.micinf.2024.105423

Rocío Rubio , Dídac Macià , Diana Barrios , Marta Vidal , Alfons Jiménez , Luis M. Molinos-Albert , Natalia Díaz , Mar Canyelles , Maria Lara-Escandell , Cyril Planchais , Pere Santamaria , Carlo Carolis , Luis Izquierdo , Ruth Aguilar , Gemma Moncunill , Carlota Dobaño

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) studies usually rely on cross-sectional data of large cohorts but limited repeated samples, overlooking significant inter-individual antibody kinetic differences. By combining Luminex, activation-induced marker (AIM) and IFN-γ/IL-2 Fluorospot assays, we characterized the IgM, IgA, and IgG antibody kinetics using 610 samples from 31 healthy adults over two years after COVID-19 vaccination, and the T-cell responses six months post-booster. Antibody trajectories varied among isotypes: IgG decayed slowly, IgA exhibited an initial sharp decline, which gradually slowed down and stabilized above the seropositivity threshold. Contrarily, IgM rapidly dropped to undetectable levels after primary vaccination. Importantly, three vaccine doses induced higher and more durable anti-spike IgG and IgA levels compared to two doses, whereas infection led to the highest antibody peak and slowest antibody decay rate compared to vaccination. Comparing with ancestral virus, antibody levels recognizing Omicron subvariants had a faster antibody decay. Finally, polyfunctional T cells were positively associated with subsequent IgA responses. These results revealed distinctive antibody patterns by isotype and highlight the benefits of booster doses in enhancing and sustaining antibody responses.

严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）研究通常依赖于大型队列的横断面数据，但重复样本有限，忽略了个体间抗体动力学的显著差异。通过结合 Luminex、活化诱导标记物（AIM）和 IFN-γ/IL-2 Fluorospot 检测法，我们利用 31 名健康成人在接种 COVID-19 疫苗两年后的 610 份样本鉴定了 IgM、IgA 和 IgG 抗体动力学，并鉴定了强化后六个月的 T 细胞反应。不同异型的抗体轨迹各不相同：IgG 下降缓慢，IgA 最初急剧下降，随后逐渐放缓并稳定在血清阳性阈值以上。相反，IgM 在初次接种后迅速下降到检测不到的水平。重要的是，与接种两剂疫苗相比，接种三剂疫苗可诱导更高和更持久的抗尖峰抗体 IgG 和 IgA 水平，而与接种疫苗相比，感染可导致最高的抗体峰值和最慢的抗体衰减率。与祖先病毒相比，识别 Omicron 亚变体的抗体水平的抗体衰减速度更快。最后，多功能 T 细胞与随后的 IgA 反应呈正相关。这些结果揭示了不同异型的抗体模式，并强调了加强剂量在增强和维持抗体反应方面的益处。

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引用次数: 0

Intragenomic diversity of the small subunit rDNA gene shows limited impact on the pathogenicity of Blastocystis infection in clinical patients 小亚基 rDNA 基因的基因组内多样性对临床患者感染大疱菌的致病性影响有限

IF 2.6 4区医学 Q3 IMMUNOLOGY

Microbes and Infection

Pub Date : 2025-02-01 DOI: 10.1016/j.micinf.2024.105422

Laura Seijas-Pereda , Pamela C. Köster , Alejandro Dashti , Begoña Bailo , Isabel Guadano-Procesi , Carlos Rescalvo-Casas , Marcos Hernando-Gozalo , Juan Cuadros-González , David Carmena , Ramón Pérez-Tanoira

The clinical significance of Blastocystis sp. remains to be fully elucidated. This study assesses whether Blastocystis subtype diversity can affect the outcome of the infection and the occurrence of clinical manifestations in infected individuals. Stool samples from 219 Blastocystis-positive patients by PCR targeting the ssu rDNA gene were fully genotyped by Sanger sequencing analyses. Co-infections by other parasitic, viral, and bacterial enteropathogens were identified by molecular and culture methods. Sequence analyses revealed the presence of six Blastocystis subtypes including ST1 (21.5 %), ST2 (17.8 %), ST3 (29.7 %), ST4 (22.8 %), ST6 (5.5 %), and ST7 (2.3 %), with a single sample harbouring a ST1+ST3 co-infection (0.5 %). Multivariate risk factor analyses using logistic regression models indicated that neither Blastocystis subtypes nor patient-associated variables including sex, country of origin, travelling history, and presence of nonspecific symptoms were positively associated with a higher likelihood of developing gastrointestinal symptoms (abdominal pain and diarrhoea). However, being of a young age (p-value: 0.003) and experiencing skin pruritus (p-value < 0.001) and eosinophilia (p-value: 0.016) were found to increase the odds of presenting gastrointestinal symptoms. Blastocystis subtypes based on variability within the ssu rDNA gene do not seem to be the main drivers of clinical manifestations in the surveyed clinical population.

Blastocystis sp.的临床意义仍有待全面阐明。本研究评估了大肠囊虫亚型多样性是否会影响感染结果以及感染者临床表现的发生。通过针对 ssu rDNA 基因的 PCR 对 219 名大疱菌阳性患者的粪便样本进行了 Sanger 测序分析。通过分子和培养方法确定了其他寄生虫、病毒和细菌肠道病原体的合并感染。序列分析表明存在六种子囊虫亚型，包括 ST1（21.5%）、ST2（17.8%）、ST3（29.7%）、ST4（22.8%）、ST6（5.5%）和 ST7（2.3%），其中一个样本存在 ST1+ST3 合并感染（0.5%）。利用逻辑回归模型进行的多变量风险因素分析表明，无论是布氏囊虫亚型还是患者相关变量（包括性别、原籍国、旅行史和出现非特异性症状），都与出现胃肠道症状（腹痛和腹泻）的可能性无关。然而，年轻（p 值：0.003）、皮肤瘙痒（p 值：0.001）和嗜酸性粒细胞增多（p 值：0.016）会增加出现胃肠道症状的几率。在接受调查的临床人群中，基于 ssu rDNA 基因内变异性的子囊虫亚型似乎并不是临床表现的主要驱动因素。

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引用次数: 0

CD4, but not Cxcr6, is necessary for control of Pneumocystis murina infection CD4而非 Cxcr6 是控制鼠肺孢子菌感染的必要条件

IF 2.6 4区医学 Q3 IMMUNOLOGY

Microbes and Infection

Pub Date : 2025-02-01 DOI: 10.1016/j.micinf.2024.105408

Lisa R. Bishop , Matthew F. Starost , Joseph A. Kovacs

CD4+ T cells are critical to control of Pneumocystis infection, and Cxcr6 has been shown to be upregulated in these cells during infection, but the roles of CD4 and Cxcr6 in this setting are undefined. To explore this, mice deficient in CD4 or Cxcr6 expression were utilized in a co-housing mouse model that mimics the natural route of Pneumocystis infection. Organism load and anti-Pneumocystis antibodies were assayed over time, and immunohistochemistry, flow cytometry, and quantitative PCR were used to characterize host immune responses during infection. CD4 was found to be necessary for clearance of Pneumocystis murina, though partial control was seen in it's absence; based on ThPOK expression, double negative T cells with T helper cell characteristics may be contributing to this control. Using a Cxcr6 deficient mouse expressing gfp, control of infection in the absence of Cxcr6 was similar to that in heterozygous control mice. It is noteworthy that gfp + cells were seen in the lungs with similar frequencies between the 2 strains. Interferon-ɣ and chemokine/ligands Cxcr3, Cxcl9, and Cxcl10 increased during P. murina infection in all models. Thus, CD4, but not Cxcr6, is needed for clearance of P. murina infection.

CD4+ T 细胞对控制肺孢子虫感染至关重要，而 Cxcr6 已被证明在感染期间在这些细胞中上调，但 CD4 和 Cxcr6 在这种情况下的作用尚未明确。为了探究这一问题，我们在一个模拟肺孢子虫自然感染途径的共居小鼠模型中利用了缺乏 CD4 或 Cxcr6 表达的小鼠。随着时间的推移，对病原体载量和抗肺孢子虫抗体进行检测，并使用免疫组化、流式细胞术和定量 PCR 分析感染期间宿主免疫反应的特征。研究发现，CD4 是清除 P. murina 的必要条件，但在 CD4 缺失的情况下也能看到部分控制；根据 ThPOK 的表达，具有 T 辅助细胞特征的双阴性 T 细胞可能有助于这种控制。使用表达 gfp 的 Cxcr6 缺陷小鼠，在没有 Cxcr6 的情况下，感染控制与杂合对照小鼠相似。值得注意的是，两种品系的小鼠肺部出现 gfp+ 细胞的频率相似。在所有模型中，干扰素ɣ和趋化因子/配体 Cxcr3、Cxcl9 和 Cxcl10 在鼠疫感染期间都有所增加。因此，清除鼠疫感染需要 CD4，而不是 Cxcr6。

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引用次数: 0

S100A12 inhibits Streptococcus pneumoniae and aids in wound healing of corneal epithelial cells both in vitro and in vivo S100A12 可抑制肺炎链球菌，并有助于角膜上皮细胞的体外和体内伤口愈合。

IF 2.6 4区医学 Q3 IMMUNOLOGY

Microbes and Infection

Pub Date : 2025-02-01 DOI: 10.1016/j.micinf.2024.105421

Priyasha Mishra , Sanjay Ch , Abhijit Ghosh , Srijita Kundu , Riddhi Agarwal , Bharathi Bhogapurapu , Swati Biswas , Sanhita Roy

Streptococcus pneumoniae, a leading cause of corneal infections worldwide, are extremely aggressive despite antibiotic sensitivity and exhibit increased resistance towards antibiotics. Antimicrobial peptides are often considered as potent alternatives against antibiotic resistance and here we have investigated the possible roles of S100A12, a host defense peptide, in wound healing and S. pneumoniae infection. S100A12 significantly inhibited growth of S. pneumoniae by disruption of membrane integrity along with increased generation of reactive oxygen species. Additionally, S100A12 accelerated cell migration and wound closure in human corneal epithelial cells and in a murine corneal wound model by activation of EGFR and MAPK signaling pathways.

肺炎链球菌是全球角膜感染的主要病因，尽管对抗生素敏感，但其攻击性极强，而且对抗生素的耐药性也在增强。抗菌肽通常被认为是对抗抗生素耐药性的有效替代品，我们在此研究了宿主防御肽 S100A12 在伤口愈合和肺炎链球菌感染中可能发挥的作用。S100A12 通过破坏膜完整性和增加活性氧的生成，明显抑制了肺炎双球菌的生长。此外，S100A12 还能通过激活表皮生长因子受体和 MAPK 信号通路，加速人角膜上皮细胞和小鼠角膜伤口模型的细胞迁移和伤口闭合。

引用次数: 0

Single-cell transcriptome analysis of the early immune response in the lymph nodes of Borrelia burgdorferi-infected mice 包柔氏菌感染小鼠淋巴结早期免疫反应的单细胞转录组分析。

IF 2.6 4区医学 Q3 IMMUNOLOGY

Microbes and Infection

Pub Date : 2025-02-01 DOI: 10.1016/j.micinf.2024.105424

Varpu Rinne , Kirsi Gröndahl-Yli-Hannuksela , Ruth Fair-Mäkelä , Marko Salmi , Pia Rantakari , Tapio Lönnberg , Jukka Alinikula , Annukka Pietikäinen , Jukka Hytönen

Lyme borreliosis is a disease caused by Borrelia burgdorferi sensu lato bacteria. Borrelia burgdorferi is known to induce prolonged extrafollicular immune responses and abnormal germinal centre formation. The infection fails to generate a neutralizing type of immunity, eventually establishing a persistent infection. Here, we performed single-cell RNA sequencing to characterize the immune landscape of lymph node lymphocytes during the early Borrelia burgdorferi infection in a murine model.

Our results indicate key features of an extrafollicular immune response four days after Borrelia burgdorferi infection, including notable B cell proliferation, immunoglobulin class switching to IgG3 and IgG2b isotypes, plasmablast differentiation, and the presence of extrafollicular B cells identified through immunohistochemistry. Additionally, we found infection-derived upregulation of suppressor of cytokine signalling genes Socs1 and Socs3, along with downregulation of genes associated with MHC II antigen presentation in B cells.

Our results support the central role of B cells in the immune response of a Borrelia burgdorferi infection, and provide cues of mechanisms behind the determination between extrafollicular and germinal centre responses during Borrelia burgdorferi infection.

莱姆包虫病是一种由常染色体包柔氏包虫引起的疾病。众所周知，包柔氏菌会诱发长时间的滤泡外免疫反应和异常生殖中心的形成。这种感染无法产生中和类型的免疫，最终形成持续感染。在这里，我们进行了单细胞 RNA 测序，以描述小鼠模型在早期感染包柔氏包虫病期间淋巴结淋巴细胞的免疫状况。我们的研究结果表明，鲍瑞氏菌感染四天后，淋巴结外免疫反应的关键特征包括显著的B细胞增殖、免疫球蛋白类别向IgG3和IgG2b同型转换、浆细胞分化以及通过免疫组化鉴定的淋巴结外B细胞的存在。此外，我们还发现感染导致细胞因子信号抑制基因 Socs1 和 Socs3 上调，以及 B 细胞中与 MHC II 抗原递呈相关的基因下调。我们的研究结果证明了 B 细胞在包柔氏菌感染的免疫反应中的核心作用，并提供了包柔氏菌感染期间决定滤泡外反应和生殖中心反应的机制线索。

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引用次数: 0

Suppressive effects of toll-like receptor 2, toll-like receptor 4, and toll-like receptor 7 on protective responses to Mycobacterium bovis BCG from epithelial cells Toll-Like Receptor 2、Toll-Like Receptor 4 和 Toll-Like Receptor 7 对上皮细胞卡介苗分枝杆菌保护性反应的抑制作用。

IF 2.6 4区医学 Q3 IMMUNOLOGY

Microbes and Infection

Pub Date : 2025-02-01 DOI: 10.1016/j.micinf.2024.105428

Aarti Singh, Akshita Singh, Shakuntala Surender Kumar Saraswati, Ankush Kumar Rana, Aayushi Singh, Chaitenya Verma, Vishal Sinha, Kanika Kalra, Krishnamurthy Natarajan

Mycobacteria have several mechanisms for evasion of protective responses mounted by the host. In this study, we unravel yet another mechanism that is mediated by Toll-Like Receptors TLR2, TLR4, and TLR7 in epithelial cells. We show that mycobacterial infection of epithelial cells increases the expression of TLR2, TLR4, and TLR7. Stimulation of either TLR along with mycobacterial infection results in an inhibition of oxidative burst resulting in increased survival of mycobacteria inside epithelial cells. TLR stimulation along with mycobacterial infection also inhibits activation of epithelial cells for T cell responses by differentially regulating the activation of ERK-MAPK and p38-MAPK along with inhibition of co-stimulatory molecule CD86 expression. Furthermore, stimulation of either TLR inhibits the induction of apoptosis and autophagy. Knockdown of either TLR by specific siRNAs reverses the inhibition by ROS and apoptosis by mycobacteria and results in reduced intracellular survival of mycobacteria in a MyD88-dependent manner. These results point towards a negative role for TLR2, TLR4, and TLR7 in regulating protective responses to M. bovis BCG infection in epithelial cells.

分枝杆菌有几种逃避宿主保护性反应的机制。在本研究中，我们揭示了由上皮细胞中的 Toll-Like 受体 TLR2、TLR4 和 TLR7 介导的另一种机制。我们发现，分枝杆菌感染上皮细胞会增加 TLR2、TLR4 和 TLR7 的表达。在分枝杆菌感染的同时刺激其中一个 TLR，可抑制氧化猝灭，从而提高分枝杆菌在上皮细胞内的存活率。在分枝杆菌感染的同时刺激 TLR，还能通过不同程度地调节 ERK-MAPK 和 p38-MAPK 的活化，抑制共刺激分子 CD86 的表达，从而抑制上皮细胞对 T 细胞反应的活化。此外，刺激任一 TLR 都会抑制细胞凋亡和自噬的诱导。通过特异性 siRNAs 敲除任一 TLR 可逆转分枝杆菌对 ROS 和细胞凋亡的抑制作用，并以 MyD88 依赖性方式降低分枝杆菌在细胞内的存活率。这些结果表明，TLR2、TLR4 和 TLR7 在调节上皮细胞对牛杆菌卡介苗感染的保护性反应中起着负作用。

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引用次数: 0

Replication-deficient Sendai virus expressing human norovirus capsid protein elicits robust NoV-specific antibody and T-cell responses in mice 表达人类诺瓦克病毒壳蛋白的复制缺陷型 sentai 病毒可在小鼠体内引起强大的诺瓦克病毒特异性抗体和 T 细胞反应。

IF 2.6 4区医学 Q3 IMMUNOLOGY

Microbes and Infection

Pub Date : 2025-02-01 DOI: 10.1016/j.micinf.2024.105412

Yazdan Samieipour , Marian Wiegand , Elena M. Willner , Dieter Hoffmann , Kamyar Shameli , Ulrike Protzer , Hassan Moeini

Human norovirus (HuNoV) is a major global cause of acute gastroenteritis, with vaccine development facing several challenges. Despite years of research, there are currently no licensed vaccines available for controlling HuNoVs. Here, we describe the construction and testing of a replication-deficient Sendai virus (SeV) vector as a potential vaccine candidate against the HuNoV GII.4 genotype. SeV was chosen as the vaccine backbone due to its non-pathogenic nature in humans, its capability for long-term antigen expression in mammalian cells, and its suitability for mucosal administration. By inserting the HuNoV GII.4 capsid gene, VP1, into the SeV genome, we generated a replication-deficient SeV (SeV/dP.VP1) vector. The resultant SeV/dP.VP1 virus were observed to successfully express the inserted NoV VP1 gene upon infection. Inoculating the vaccine into wild-type mice elicited NoV-specific IgG antibodies, along with INF-γ and IL-2-producing T cells, through both intranasal (i.n.) and intramuscular (i.m.) immunization. Furthermore, a significant level of NoV-specific IgA was detected in lung homogenates after i.n. immunization, particularly using a high dose of the viral vector. Additionally, a synergistic effect was observed with heterologous prime-boost regimens using SeV/dP.VP1 and MVA.VP1 vectors, indicating the potential for more robust immune responses when the vaccine design is optimized. Our study demonstrates the potential of a SeV vaccine candidate in eliciting a broad immune response and lays the foundation for further exploration of the SeV vector platform's potential as a HuNoV vaccine. Additionally, the results emphasize the importance of vaccine dosage and administration route, highlighting the need for tailored immunization strategies.

人类诺如病毒（HuNoV）是全球急性肠胃炎的主要病因，其疫苗开发面临着诸多挑战。尽管进行了多年的研究，但目前还没有可用于控制 HuNoV 的特许疫苗。在此，我们介绍了一种复制缺陷仙台病毒（SeV）载体的构建和测试情况，该载体是针对 HuNoV GII.4 基因型的潜在候选疫苗。选择 SeV 作为疫苗骨架是因为它对人类无致病性，能在哺乳动物细胞中长期表达抗原，而且适合粘膜给药。通过在 SeV 基因组中插入 HuNoV GII.4 荚膜基因 VP1，我们产生了一种复制缺陷 SeV（SeV/dP.VP1）载体。据观察，由此产生的 SeV/dP.VP1 病毒在感染后能成功表达插入的 NoV VP1 基因。通过鼻内（i.n.）和肌肉注射（i.m.）免疫，将疫苗接种到野生型小鼠体内可激发 NoV 特异性 IgG 抗体以及 INF-γ 和 IL-2 产T细胞。此外，鼻内免疫后，特别是使用高剂量的病毒载体免疫后，在肺匀浆中检测到了大量的NoV特异性IgA。此外，使用 SeV/dP.VP1 和 MVA.VP1 病毒载体的异源素体增强方案还观察到了协同效应，这表明疫苗设计优化后有可能产生更强的免疫反应。我们的研究证明了 SeV 候选疫苗在激发广泛免疫应答方面的潜力，并为进一步探索 SeV 载体平台作为 HuNoV 疫苗的潜力奠定了基础。此外，研究结果还强调了疫苗剂量和给药途径的重要性，突出了定制免疫策略的必要性。

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引用次数: 0

LPS-LBP complex induced endothelial cell pyroptosis in aortic dissection is associated with gut dysbiosis 主动脉夹层中 LPS-LBP 复合物诱导的内皮细胞脓毒症与肠道菌群失调有关

IF 2.6 4区医学 Q3 IMMUNOLOGY

Microbes and Infection

Pub Date : 2025-02-01 DOI: 10.1016/j.micinf.2024.105406

Gulinazi Yesitayi , Qi Wang , Mengmeng Wang , Mierxiati Ainiwan , Kaisaierjiang Kadier , Aliya Aizitiaili , Yitong Ma , Xiang Ma

Acute aortic dissection (AAD) is the most severe traumatic disease affecting the aorta. Pyroptosis-mediated vascular wall inflammation is a crucial trigger for AAD, and the exact mechanism requires further investigation. In this study, our proteomic analysis showed that Lipopolysaccharide (LPS)-binding protein (LBP) was significantly upregulated in the plasma and aortic tissue of patients with AAD. Further, 16S rRNA sequencing of stool samples suggested that patients with AAD exhibit gut dysbiosis, which may lead to an impaired intestinal barrier and LPS leakage. By comparing with control mice, we found that LBP, including Pyrin Domain Containing Protein3 (NLRP3), the CARD-containing adapter apoptosis-associated speck-like protein (ASC), and Cleaved caspase-1, were upregulated in the AAD aorta, whereas gut intestinal barrier-related proteins were downregulated. Moreover, treated with LBPK95A (an LBP inhibitor) attenuated the incidence of AAD, the expression levels of pyroptosis-related factors, and the extent of vascular pathological changes compared to those in AAD mice. In addition, LPS and LBP treatment of human umbilical vein endothelial cells (HUVECs) activated TLR4 signaling and intracellular reactive oxygen species (ROS) production, which stimulated NLRP3 inflammasome formation and mediated pyroptosis in endothelial cells. Our findings showed that gut dysbiosis mediates pyroptosis by the LPS-LBP complex, thus providing new insights into developing AAD.

急性主动脉夹层（AAD）是影响主动脉的最严重创伤性疾病。热蛋白沉积介导的血管壁炎症是诱发急性主动脉夹层的关键因素，其确切机制有待进一步研究。本研究的蛋白质组分析显示，AAD 患者血浆和主动脉组织中的脂多糖（LPS）结合蛋白（LBP）明显上调。此外，粪便样本的 16S rRNA 测序表明，AAD 患者的肠道菌群失调可能导致肠道屏障受损和 LPS 泄漏。通过与对照组小鼠进行比较，我们发现枸杞多糖（包括 Pyrin Domain Containing Protein3，NLRP3）、含 CARD 的适配器凋亡相关斑点样蛋白（apoptosis-associated speck-like protein，ASC）和裂解的 caspase-1 在 AAD 主动脉中上调，而肠道屏障相关蛋白下调。此外，与 AAD 小鼠相比，用 LBPK95A（一种 LBP 抑制剂）治疗可减轻 AAD 的发病率、热噬相关因子的表达水平以及血管病理变化的程度。此外，LPS和LBP处理人脐静脉内皮细胞（HUVECs）激活了TLR4信号传导和细胞内活性氧（ROS）的产生，从而刺激了NLRP3炎性体的形成并介导了内皮细胞的热蛋白沉积。我们的研究结果表明，肠道菌群失调通过 LPS-LBP 复合物介导了热蛋白沉积，从而为 AAD 的发展提供了新的见解。

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