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High dose inactivated influenza vaccine inconsistently improves heterologous antibody responses in an elderly human cohort 高剂量灭活流感疫苗在老年人队列中不一致地改善异源抗体反应
Pub Date : 2025-01-07 DOI: 10.1093/infdis/jiaf003
W Zane Billings, Yang Ge, Jessica H Knight, Hayley Hemme, Savannah M Hammerton, Amanda L Skarlupka, Wangnan Cao, Ye Shen, Justin Bahl, Paul G Thomas, Ted M Ross, Andreas Handel
Background Older adults often mount a weak immune response to standard inactivated influenza vaccines. To induce a stronger response and better protection, a high-dose (HD) version of the inactivated Fluzone vaccine is recommended for individuals >65 years of age. While better immunogenicity and protection against the vaccine strain has been shown, it is not known if the HD vaccine also induces a robust antibody response to heterologous strains. Methods We fit bayesian multilevel regression models to hemagglutination inhibition (HAI) antibody data from an influenza vaccine cohort spanning the 2013/14-2021/22 influenza seasons. We used this model to estimate the average causal effect (ACE) of obtaining the HD vaccine, relative to the SD vaccine. Results We show that while there is generally a benefit derived from the HD vaccine, the impact is small and inconsistent. For some strains, the HD vaccine might even result in less robust heterologous responses. Conclusions We suggest that further increases in dose might be worth investigating to help induce a stronger broad response.
背景:老年人对标准灭活流感疫苗的免疫反应往往较弱。为了引起更强的反应和更好的保护,建议65岁以上的人使用高剂量(HD)灭活疫苗。虽然已显示出更好的免疫原性和对疫苗株的保护作用,但尚不清楚HD疫苗是否也能诱导对异源菌株的强大抗体反应。方法采用贝叶斯多水平回归模型对2013/14-2021/22流感季节流感疫苗队列的血凝抑制(HAI)抗体数据进行拟合。我们使用该模型来估计获得HD疫苗相对于SD疫苗的平均因果效应(ACE)。我们表明,虽然HD疫苗总体上有益处,但影响很小且不一致。对于某些毒株,HD疫苗甚至可能导致较弱的异源反应。我们认为进一步增加剂量可能值得研究,以帮助诱导更强的广泛反应。
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引用次数: 0
Cobalt chloride-mimicked hepatocyte cell hypoxia induces TREX1 leading to Hepatitis B virus restriction 氯化钴模拟肝细胞细胞缺氧诱导TREX1导致乙型肝炎病毒限制
Pub Date : 2025-01-07 DOI: 10.1093/infdis/jiaf002
Rodolphe Suspène, Vincent Caval, Pierre Khalfi, Emmanuelle Pitré, Agnès Marchio, Pascal Pineau, Jean-Pierre Vartanian
Background Restriction factors are host cell proteins that play a role in limiting virus replication. They form part of the intrinsic immune system and function as a first line of defense against viral infections. Hepatitis B virus (HBV) does not escape this rule and TREX1, a host restriction enzyme acts as an antiviral factor, leading to the inhibition of the virus. Methods TREX1-expressing constructs were generated and modified by site-directed mutagenesis. The location and activity of the different TREX1 constructs were analyzed by Immunofluorescence and FACS. HepaD38 cells were either transfected or transduced with the different TREX1 constructs in presence or absence of cobalt chloride-mimicked hypoxia and released HBV was quantified by qPCR. Results We identified TREX1 as a restriction factor that suppresses HBV replication. Furthermore, TREX1 expression was increased in the presence of cobalt chloride, a chemical agent mimicking hypoxia. Thus, by treating cells with cobalt chloride, TREX1 reduced HBV replication by a factor of 2, demonstrating that under hypoxic conditions, TREX1 restricts HBV replication. Finally, an analysis of 36 HBV-infected patients with hepatocellular carcinoma revealed that TREX1 expression was inversely correlated to the HBV viral and HBV cccDNA. Conclusion Current treatments are unable to eliminate HBV genomic reservoirs, which persist as covalently closed episomal circular DNA. TREX1 is a novel restriction factor that blocks HBV replication. It would be therapeutically relevant to study whether HBV nucleocapsid recycling containing TREX1 enzyme could be released into the nucleus and degrade the viral and nuclear DNA of infected cells.
限制性因子是在限制病毒复制中起作用的宿主细胞蛋白。它们是内在免疫系统的一部分,是抵御病毒感染的第一道防线。乙型肝炎病毒(HBV)不能逃脱这一规则,宿主限制性内切酶TREX1作为抗病毒因子,导致病毒受到抑制。方法利用位点定向诱变技术对表达trex1的构建体进行修饰。利用免疫荧光和FACS分析不同TREX1构建体的位置和活性。在存在或不存在氯化钴模拟缺氧的情况下,用不同TREX1构建体转染或转导HepaD38细胞,并通过qPCR定量释放HBV。结果我们确定TREX1是抑制HBV复制的限制性因子。此外,TREX1的表达在氯化钴(一种模拟缺氧的化学剂)存在下增加。因此,通过用氯化钴处理细胞,TREX1以2倍的倍数减少HBV复制,表明在缺氧条件下,TREX1限制HBV复制。最后,对36例HBV感染的肝细胞癌患者的分析显示TREX1表达与HBV病毒和HBV cccDNA呈负相关。结论目前的治疗方法无法消除HBV基因组储存库,这些储存库以共价封闭的外体环状DNA形式存在。TREX1是一种新的抑制HBV复制的限制性因子。研究含有TREX1酶的HBV核衣壳回收能否释放到细胞核中并降解感染细胞的病毒和核DNA,将具有治疗意义。
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引用次数: 0
Distinguishing Multisystem Inflammatory Syndrome in Children from Typhus Using Artificial Intelligence: MIS-C vs. Endemic Typhus (AI-MET) 应用人工智能鉴别儿童斑疹伤寒多系统炎症综合征:MIS-C与地方性斑疹伤寒(AI-MET)
Pub Date : 2025-01-07 DOI: 10.1093/infdis/jiaf004
Angela Chun, Abraham Bautista-Castillo, Isabella Osuna, Kristiana Nasto, Flor M Munoz, Gordon E Schutze, Sridevi Devaraj, Eyal Muscal, Marietta M de Guzman, Kristen Sexson Tejtel, Tiphanie P Vogel, Ioannis A Kakadiaris
Background The pandemic emergent disease multisystem inflammatory syndrome in children (MIS-C) following coronavirus disease-19 infection can mimic endemic typhus. We aimed to use artificial intelligence (AI) to develop a clinical decision support system that accurately distinguishes MIS-C versus Endemic Typhus (MET). Methods Demographic, clinical, and laboratory features rapidly available following presentation were extracted for 133 patients with MIS-C and 87 patients hospitalized due to typhus. An attention module assigned importance to inputs used to create the two-phase AI-MET. Phase 1 uses 17 features to arrive at a classification manually (MET-17). If the confidence level is not surpassed, 13 additional features are added to calculate MET-30 using a recurrent neural network. Results While 24 of 30 features differed statistically, the values overlapped sufficiently that the features were clinically irrelevant distinguishers as individual parameters. However, AI-MET successfully classified typhus and MIS-C with 100% accuracy. A validation cohort of 111 additional patients with MIS-C was classified with 99% accuracy. Conclusions Artificial intelligence can successfully distinguish MIS-C from typhus using rapidly available features. This decision support system will be a valuable tool for front-line providers facing the difficulty of diagnosing a febrile child in endemic areas.
背景冠状病毒covid -19感染后的儿童大流行突发性疾病多系统炎症综合征(MIS-C)可模拟地方性斑疹伤寒。我们的目标是利用人工智能(AI)开发一个临床决策支持系统,准确区分misc与地方性斑疹伤寒(MET)。方法对133例misc患者和87例因斑疹伤寒住院的患者进行人口统计学、临床和实验室特征分析。注意力模块为用于创建两阶段AI-MET的输入分配重要性。阶段1使用17个特征来手动到达一个分类(MET-17)。如果未超过置信水平,则使用递归神经网络添加13个附加特征来计算MET-30。结果虽然30个特征中有24个有统计学差异,但这些特征的重叠程度足以使其成为临床无关的个体参数。然而,AI-MET成功地以100%的准确率对斑疹伤寒和misc进行了分类。另外111例misc患者的验证队列分类准确率为99%。结论人工智能可以利用快速获取的特征成功地将MIS-C与斑疹伤寒区分开来。这一决策支持系统将成为在流行地区面临诊断发热儿童困难的一线提供者的宝贵工具。
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引用次数: 0
Helminth infection induces innate immune priming in plasmacytoid dendritic cells 蠕虫感染诱导浆细胞样树突状细胞的先天免疫启动
Pub Date : 2025-01-07 DOI: 10.1093/infdis/jiaf009
Lamin B Cham, Bradley Whitehead, Marvin Werner, Frederikke Jensen, Mads Zippor, Trine H Mogensen, Mihai G Netea, Andrew R Williams, Peter Nejsum
Heligmosomoides polygyrus co-infection is reported to have protective antiviral effects against pulmonary viral infections. To investigate a potential underlying mechanism, we infected C57BL/6 mice with H. polygyrus larvae for two weeks. Bone marrow (BM)-derived plasmacytoid dendritic cells (pDCs) were generated and stimulated with TLR agonists. We found increased expression of type 1 interferon genes (Ifnα1, Ifnα4, Ifnβ1, Mx1, Isg15), increased TNF, IL-6, IL-10 secretion, and higher expression of antigen presentation markers in BM-derived-pDCs from infected mice compared to naïve control. Our findings may partly explain the mechanism of the antiviral protection previously reported in acute helminth infections.
据报道,多回Heligmosomoides合并感染对肺部病毒感染具有保护性抗病毒作用。为了研究可能的潜在机制,我们用多回绦虫幼虫感染C57BL/6小鼠两周。产生骨髓(BM)来源的浆细胞样树突状细胞(pDCs)并使用TLR激动剂刺激。我们发现,与naïve对照组相比,感染小鼠的bm源性pdcs中1型干扰素基因(Ifnα1、Ifnα4、Ifnβ1、Mx1、Isg15)表达增加,TNF、IL-6、IL-10分泌增加,抗原呈递标志物表达增加。我们的发现可能部分解释了先前报道的急性蠕虫感染的抗病毒保护机制。
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引用次数: 0
Phage-Encoded Virulence Factor, Gp05, Alters Membrane Phospholipids and Reduces Antimicrobial Susceptibility in Methicillin-Resistant Staphylococcus aureus 噬菌体编码毒力因子Gp05改变膜磷脂并降低耐甲氧西林金黄色葡萄球菌的抗菌敏感性
Pub Date : 2024-12-31 DOI: 10.1093/infdis/jiae640
Yi Li, Nagendra N Mishra, Liang Chen, Adhar C Manna, Ambrose L Cheung, Richard A Proctor, Yan Q Xiong
Background Methicillin-resistant Staphylococcus aureus (MRSA) is a leading pathogen causing severe endovascular infections. The prophage-encoded protein Gp05 has been identified as a critical virulence factor that contributes to MRSA persistence during vancomycin (VAN) treatment in an experimental endocarditis model. However, the underlining mechanisms driving this persistence phenotype remain poorly understood. Methods The current study aimed to elucidate the genetic factors contributing to Gp05-associated MRSA persistence by utilizing RNA sequencing (RNA-seq) on an isogenic MRSA strain set, including a clinical persistent bacteremia isolate (PB 300-169), its isogenic chromosomal gp05 deletion mutant, and gp05-complemented strains. Results RNA-seq analysis revealed significantly downregulation of the graSR-vraFG regulatory system and its downstream genes, mprF and dltABCD, in the gp05 deletion mutant compared to the wild-type and gp05-complemented strains. Notably, this downregulation led to a substantial shift in cell membrane composition, with a marked increase in negatively charged phosphatidylglycerol (PG) and a concomitant decrease in positively charged lysyl-PG (LPG). These changes in membrane lipid composition resulted in increased susceptibility of the gp05 deletion mutant to human cationic antimicrobial peptide (CAMP) LL-37, polymorphonuclear neutrophil (PMN) and VAN. Similar findings were observed in an isogenic gp05 overexpression strain set with different genetic background (MRSA USA300 JE2). Conclusions These findings suggest that Gp05 plays a pivotal role in MRSA persistence by modulating cell surface components and surface charge. This study provides new insights into the molecular mechanisms underlying Gp05-mediated persistence in MRSA endovascular infections and highlights potential therapeutic targets to combat persistent MRSA infections.
耐甲氧西林金黄色葡萄球菌(MRSA)是引起严重血管内感染的主要病原体。在实验性心内膜炎模型中,在万古霉素(VAN)治疗期间,原噬菌体编码的蛋白Gp05被确定为MRSA持续存在的关键毒力因子。然而,驱动这种持久性表型的主要机制仍然知之甚少。方法本研究旨在通过RNA测序(RNA-seq)对一组等基因MRSA菌株进行分析,包括临床持续性菌血症分离株(PB 300-169)、其等基因染色体gp05缺失突变株和gp05补充菌株,以阐明gp05相关MRSA持久性的遗传因素。结果RNA-seq分析显示,与野生型和gp05补充型相比,gp05缺失突变体中graSR-vraFG调控系统及其下游基因mprF和dltABCD显著下调。值得注意的是,这种下调导致细胞膜组成发生实质性变化,带负电荷的磷脂酰甘油(PG)显著增加,同时带正电荷的赖基-PG (LPG)减少。这些膜脂组成的变化导致gp05缺失突变体对人阳离子抗菌肽(CAMP) LL-37、多形核中性粒细胞(PMN)和VAN的易感性增加。在不同遗传背景的gp05过表达等基因菌株(MRSA USA300 JE2)中也观察到类似的结果。结论Gp05通过调节细胞表面成分和表面电荷,在MRSA持续存在中起关键作用。这项研究为gp05介导的MRSA血管内感染持续存在的分子机制提供了新的见解,并强调了对抗MRSA持续感染的潜在治疗靶点。
{"title":"Phage-Encoded Virulence Factor, Gp05, Alters Membrane Phospholipids and Reduces Antimicrobial Susceptibility in Methicillin-Resistant Staphylococcus aureus","authors":"Yi Li, Nagendra N Mishra, Liang Chen, Adhar C Manna, Ambrose L Cheung, Richard A Proctor, Yan Q Xiong","doi":"10.1093/infdis/jiae640","DOIUrl":"https://doi.org/10.1093/infdis/jiae640","url":null,"abstract":"Background Methicillin-resistant Staphylococcus aureus (MRSA) is a leading pathogen causing severe endovascular infections. The prophage-encoded protein Gp05 has been identified as a critical virulence factor that contributes to MRSA persistence during vancomycin (VAN) treatment in an experimental endocarditis model. However, the underlining mechanisms driving this persistence phenotype remain poorly understood. Methods The current study aimed to elucidate the genetic factors contributing to Gp05-associated MRSA persistence by utilizing RNA sequencing (RNA-seq) on an isogenic MRSA strain set, including a clinical persistent bacteremia isolate (PB 300-169), its isogenic chromosomal gp05 deletion mutant, and gp05-complemented strains. Results RNA-seq analysis revealed significantly downregulation of the graSR-vraFG regulatory system and its downstream genes, mprF and dltABCD, in the gp05 deletion mutant compared to the wild-type and gp05-complemented strains. Notably, this downregulation led to a substantial shift in cell membrane composition, with a marked increase in negatively charged phosphatidylglycerol (PG) and a concomitant decrease in positively charged lysyl-PG (LPG). These changes in membrane lipid composition resulted in increased susceptibility of the gp05 deletion mutant to human cationic antimicrobial peptide (CAMP) LL-37, polymorphonuclear neutrophil (PMN) and VAN. Similar findings were observed in an isogenic gp05 overexpression strain set with different genetic background (MRSA USA300 JE2). Conclusions These findings suggest that Gp05 plays a pivotal role in MRSA persistence by modulating cell surface components and surface charge. This study provides new insights into the molecular mechanisms underlying Gp05-mediated persistence in MRSA endovascular infections and highlights potential therapeutic targets to combat persistent MRSA infections.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A core glycolipid vaccine elicits cross-reactive antibodies against Salmonella spp. and protects against invasive nontyphoidal Salmonella disease in mice 一种核心糖脂疫苗可诱导抗沙门氏菌交叉反应抗体,并保护小鼠免受侵袭性非伤寒沙门氏菌病的侵袭
Pub Date : 2024-12-31 DOI: 10.1093/infdis/jiae641
Scott M Baliban, Surekha Shridhar, Kun Luo, Jacqueline Kolasny, Sang Hyun, Zhiyong Zhao, Sharon M Tennant, Alan S Cross
Background Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A in addition to gastroenteritis and invasive disease, predominantly attributable to nontyphoidal Salmonella serovars Typhimurium and Enteritidis, are major causes of death and disability across the globe. A broad-spectrum vaccine that protects against disease caused by typhoidal and nontyphoidal serovars of Salmonella is not available for humans but would prevent a considerable burden of disease worldwide. Methods We previously developed a broad-spectrum vaccine for Gram-negative bacteria that is based on the inner core domain of detoxified Escherichia coli O111, Rc (J5) mutant lipooligosaccharide, a highly conserved antigen across Gram-negative bacteria, complexed with an outer membrane protein of group B Neisseria meningitidis. In this study, mice and rabbits were immunized with the J5 core/outer membrane protein subunit vaccine. We assessed the cross-reactivity of antisera with various Salmonella species lipopolysaccharides and the protective efficacy of passive and active immunization with J5 vaccine against experimental nontyphoidal Salmonella infection in mice. Results Vaccination with J5 induced IgG responses that strongly recognized lipopolysaccharide from both typhoidal and nontyphoidal Salmonella and imparted a survival benefit against lethal heterologous challenges with S. Typhimurium and S. Enteritidis. Additionally, passive transfer studies with rabbit hyperimmune sera raised against the J5 vaccine revealed that anti-core antibodies were protective against lipopolysaccharide challenge in D-galactosamine-sensitized mice. Conclusions Our findings support the development of core glycolipids as a novel Salmonella vaccine candidate. Further investigation is warranted to determine the efficacy of the J5 core/outer membrane protein vaccine against other Salmonella serovars of concern.
背景:除肠胃炎和侵袭性疾病外,主要由非伤寒沙门氏菌伤寒和肠炎引起的伤寒沙门氏菌血清型和副伤寒沙门氏菌引起的肠热是全球死亡和残疾的主要原因。一种广谱疫苗可以预防由伤寒和非伤寒沙门氏菌血清型引起的疾病,目前尚无法用于人类,但可以在世界范围内预防相当大的疾病负担。我们先前开发了一种广谱革兰氏阴性菌疫苗,该疫苗基于解毒大肠杆菌O111, Rc (J5)突变型脂寡糖的内核结构域,这是一种在革兰氏阴性菌中高度保守的抗原,与B群脑膜炎奈瑟菌的外膜蛋白络合。本研究采用J5核心/外膜蛋白亚单位疫苗免疫小鼠和家兔。研究了抗血清与多种沙门菌脂多糖的交叉反应性,以及J5疫苗被动免疫和主动免疫对小鼠实验性非伤寒沙门菌感染的保护作用。结果接种J5诱导的IgG应答能强烈识别伤寒沙门氏菌和非伤寒沙门氏菌的脂多糖,并对鼠伤寒沙门氏菌和肠炎沙门氏菌的致死性异源攻击具有生存优势。此外,J5疫苗兔超免疫血清的被动转移研究显示,抗核心抗体对d -半乳糖胺致敏小鼠的脂多糖攻击具有保护作用。结论本研究结果支持核心糖脂作为沙门氏菌新型候选疫苗的发展。需要进一步研究以确定J5核心/外膜蛋白疫苗对其他关注的沙门氏菌血清型的有效性。
{"title":"A core glycolipid vaccine elicits cross-reactive antibodies against Salmonella spp. and protects against invasive nontyphoidal Salmonella disease in mice","authors":"Scott M Baliban, Surekha Shridhar, Kun Luo, Jacqueline Kolasny, Sang Hyun, Zhiyong Zhao, Sharon M Tennant, Alan S Cross","doi":"10.1093/infdis/jiae641","DOIUrl":"https://doi.org/10.1093/infdis/jiae641","url":null,"abstract":"Background Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A in addition to gastroenteritis and invasive disease, predominantly attributable to nontyphoidal Salmonella serovars Typhimurium and Enteritidis, are major causes of death and disability across the globe. A broad-spectrum vaccine that protects against disease caused by typhoidal and nontyphoidal serovars of Salmonella is not available for humans but would prevent a considerable burden of disease worldwide. Methods We previously developed a broad-spectrum vaccine for Gram-negative bacteria that is based on the inner core domain of detoxified Escherichia coli O111, Rc (J5) mutant lipooligosaccharide, a highly conserved antigen across Gram-negative bacteria, complexed with an outer membrane protein of group B Neisseria meningitidis. In this study, mice and rabbits were immunized with the J5 core/outer membrane protein subunit vaccine. We assessed the cross-reactivity of antisera with various Salmonella species lipopolysaccharides and the protective efficacy of passive and active immunization with J5 vaccine against experimental nontyphoidal Salmonella infection in mice. Results Vaccination with J5 induced IgG responses that strongly recognized lipopolysaccharide from both typhoidal and nontyphoidal Salmonella and imparted a survival benefit against lethal heterologous challenges with S. Typhimurium and S. Enteritidis. Additionally, passive transfer studies with rabbit hyperimmune sera raised against the J5 vaccine revealed that anti-core antibodies were protective against lipopolysaccharide challenge in D-galactosamine-sensitized mice. Conclusions Our findings support the development of core glycolipids as a novel Salmonella vaccine candidate. Further investigation is warranted to determine the efficacy of the J5 core/outer membrane protein vaccine against other Salmonella serovars of concern.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Combined Sequential Antiretroviral Therapy-Induced Immune Reconstitution Bone Loss and Estrogen Deficiency Bone Loss are Cumulative in Mice Models 联合序贯抗逆转录病毒治疗诱导的免疫重建骨质流失和雌激素缺乏骨质流失在小鼠模型中是累积性的
Pub Date : 2024-12-27 DOI: 10.1093/infdis/jiae643
Sadaf Dabeer, Ashish Kumar Tripathi, Daiana Weiss, Tatyana Vikulina, Ighovwerha Ofotokun, M Neale Weitzmann
Background Antiretroviral therapy (ART) causes osteoporosis and bone fractures, increasing morbidity and mortality in people living with HIV (PLH). ART induces immune reconstitution bone loss (IRBL), an inflammatory reaction associated with immune system reactivation. Women represent >50% of PLH, and many are now undergoing menopause, a major cause of postmenopausal osteoporosis that also increases fracture risk. However, the interactions between IRBL and postmenopausal bone loss are poorly understood and were investigated in this study. Methods We used a mouse model of IRBL, applied simultaneously or sequentially with surgical ovariectomy (Ovx), a mouse model of postmenopausal osteoporosis. Cortical and trabecular bone in vertebrae and femurs was assessed using micro-computed tomography (µCT) and bone turnover quantified by serum markers of bone resorption and formation via ELISA. T cell production of osteoclastogenic cytokines was analyzed by flow cytometry. Results Although simultaneous Ovx and IRBL did not have additive effects, sequential Ovx and IRBL caused cumulative bone loss. Vertebral bone loss from combined Ovx and IRBL (Δ=-42.6 vs. Control: p<0.01) was significantly reduced by the anti-inflammatory agent Abatacept (Δ=-13.9 vs. Control: p=not significant) and the probiotic Lactobacillus rhamnosus GG (LGG) (Δ=-8.6 vs. Control: p=not significant). Both treatments reduced bone resorption, stimulated formation, and suppressed CD4+ T cell production of the osteoclastogenic cytokines TNF-α and IL-17A. Conclusion Sequential IRBL and postmenopausal bone loss appear to be cumulative. If validated in humans, early screening and prophylaxis could reduce fracture risk in postmenopausal women living with HIV (WLH). Probiotic therapy may provide a beneficial alternative to pharmacotherapy.
背景:抗逆转录病毒治疗(ART)导致骨质疏松和骨折,增加艾滋病毒感染者(PLH)的发病率和死亡率。ART诱导免疫重建骨质流失(IRBL),一种与免疫系统再激活相关的炎症反应。女性占PLH的50%,其中许多人现在正处于更年期,这是绝经后骨质疏松症的主要原因,也增加了骨折的风险。然而,IRBL与绝经后骨质流失之间的相互作用尚不清楚,本研究对此进行了调查。方法采用小鼠IRBL模型,与卵巢切除术(Ovx)同时或先后应用,这是一种绝经后骨质疏松小鼠模型。采用微计算机断层扫描(µCT)评估椎骨和股骨的皮质骨和小梁骨,通过ELISA测定骨吸收和形成的血清标志物量化骨转换。流式细胞术分析T细胞生成破骨细胞因子。结果虽然Ovx和IRBL同时发生没有累加效应,但Ovx和IRBL相继发生可引起累积性骨质流失。抗炎剂Abatacept (Δ=-13.9 vs. Control: p=不显著)和益生菌鼠李糖乳杆菌GG (Δ=-8.6 vs. Control: p=不显著)显著减少Ovx和IRBL联合导致的椎体骨丢失(Δ=-42.6 vs. Control: p=不显著)。两种治疗均可减少骨吸收,刺激骨形成,抑制CD4+ T细胞产生破骨细胞因子TNF-α和IL-17A。结论序贯IRBL和绝经后骨质流失是累积性的。如果在人类中得到验证,早期筛查和预防可以降低绝经后感染艾滋病毒(WLH)的妇女骨折风险。益生菌疗法可能提供一种有益的替代药物治疗。
{"title":"Combined Sequential Antiretroviral Therapy-Induced Immune Reconstitution Bone Loss and Estrogen Deficiency Bone Loss are Cumulative in Mice Models","authors":"Sadaf Dabeer, Ashish Kumar Tripathi, Daiana Weiss, Tatyana Vikulina, Ighovwerha Ofotokun, M Neale Weitzmann","doi":"10.1093/infdis/jiae643","DOIUrl":"https://doi.org/10.1093/infdis/jiae643","url":null,"abstract":"Background Antiretroviral therapy (ART) causes osteoporosis and bone fractures, increasing morbidity and mortality in people living with HIV (PLH). ART induces immune reconstitution bone loss (IRBL), an inflammatory reaction associated with immune system reactivation. Women represent >50% of PLH, and many are now undergoing menopause, a major cause of postmenopausal osteoporosis that also increases fracture risk. However, the interactions between IRBL and postmenopausal bone loss are poorly understood and were investigated in this study. Methods We used a mouse model of IRBL, applied simultaneously or sequentially with surgical ovariectomy (Ovx), a mouse model of postmenopausal osteoporosis. Cortical and trabecular bone in vertebrae and femurs was assessed using micro-computed tomography (µCT) and bone turnover quantified by serum markers of bone resorption and formation via ELISA. T cell production of osteoclastogenic cytokines was analyzed by flow cytometry. Results Although simultaneous Ovx and IRBL did not have additive effects, sequential Ovx and IRBL caused cumulative bone loss. Vertebral bone loss from combined Ovx and IRBL (Δ=-42.6 vs. Control: p<0.01) was significantly reduced by the anti-inflammatory agent Abatacept (Δ=-13.9 vs. Control: p=not significant) and the probiotic Lactobacillus rhamnosus GG (LGG) (Δ=-8.6 vs. Control: p=not significant). Both treatments reduced bone resorption, stimulated formation, and suppressed CD4+ T cell production of the osteoclastogenic cytokines TNF-α and IL-17A. Conclusion Sequential IRBL and postmenopausal bone loss appear to be cumulative. If validated in humans, early screening and prophylaxis could reduce fracture risk in postmenopausal women living with HIV (WLH). Probiotic therapy may provide a beneficial alternative to pharmacotherapy.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Plasma Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Biomarkers of Cognitive Decline in People Living with HIV 血浆神经丝轻链和胶质纤维酸性蛋白作为HIV感染者认知能力下降的生物标志物
Pub Date : 2024-12-26 DOI: 10.1093/infdis/jiae623
Shibani S Mukerji, Petra Bachanová, Hemi Park, Linzy V Rosen, Rommi Kashlan, Pia Kivisäkk, Albert M Anderson, Felicia C Chow, Kunling Wu, Raha M Dastgheyb, Leah H Rubin, Katherine Tassiopoulos, Robert A Parker, Emily P Hyle
Background This study examined the relationship between neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and cognition in people living with HIV (PLWH) at baseline and over time. Methods Plasma and clinical data were available from PLWH aged ≥45 years with HIV RNA <200 copies/mL enrolled in the AIDS Clinical Trials Group HAILO cohort study. We measured plasma NfL and GFAP using a single molecule array platform. Four neuropsychological assessments, standardized to z-scores and averaged (NPZ-4), were used as a marker of cognitive function. Date of plasma collection marked study baseline; longitudinal changes in NPZ-4 were summarized by slope. Linear regressions between biomarkers and baseline NPZ-4 were adjusted for demographic factors. Regressions of longitudinal data were adjusted for baseline NPZ-4 and weighted by number of visits. Results The study included 503 participants with a median [IQR] age of 52 [48, 57] years, observation of 6 [5, 7] years, and 26% had baseline cognitive impairment defined by HAILO. Cross-sectionally, higher NfL (β=-0.76, p<0.01) and GFAP (β=-0.44, p=0.02) were associated with worse baseline NPZ-4. Longitudinally, the median [IQR] NPZ-4 slope was 0.003 [-0.06, 0.06] units/year with 48% demonstrating cognitive decline (slope<0). Higher NfL (β=-0.08, p<0.01), but not GFAP (β=-0.03, p=0.08), was associated with cognitive decline. Conclusions NfL and GFAP were associated with worse cognition cross-sectionally; only NfL was associated with longitudinal cognitive decline. However, the clinical utility of NfL and GFAP is uncertain given small effect sizes and should be studied in populations with more rapid decline (e.g., aged ≥60).
本研究探讨了HIV感染者(PLWH)的神经丝轻链(NfL)和胶质纤维酸性蛋白(GFAP)与认知在基线和随时间变化的关系。方法收集艾滋病临床试验组HAILO队列研究中年龄≥45岁、HIV RNA≥200拷贝/mL的PLWH患者的血浆和临床资料。我们使用单分子阵列平台测量血浆NfL和GFAP。四项神经心理评估,标准化为z分数和平均(NPZ-4),被用作认知功能的标记。血浆采集日期标记为研究基线;NPZ-4的纵向变化用坡度来概括。生物标志物与基线NPZ-4之间的线性回归根据人口统计学因素进行调整。对纵向数据的回归进行基线NPZ-4调整,并按就诊次数加权。结果该研究纳入503名参与者,中位[IQR]年龄为52[48,57]岁,观察时间为6[5,7]年,26%存在HAILO定义的基线认知障碍。横断面上,较高的NfL (β=-0.76, p<0.01)和GFAP (β=-0.44, p=0.02)与较差的基线NPZ-4相关。纵向上,中位[IQR] NPZ-4斜率为0.003[-0.06,0.06]单位/年,其中48%表现出认知能力下降(斜率&;lt;0)。较高的NfL (β=-0.08, p<0.01)与认知能力下降相关,但与GFAP无关(β=-0.03, p=0.08)。结论横截面上,NfL和GFAP与认知差相关;只有NfL与纵向认知能力下降有关。然而,考虑到较小的效应量,NfL和GFAP的临床应用尚不确定,应在下降更快的人群中进行研究(例如,年龄≥60岁)。
{"title":"Plasma Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Biomarkers of Cognitive Decline in People Living with HIV","authors":"Shibani S Mukerji, Petra Bachanová, Hemi Park, Linzy V Rosen, Rommi Kashlan, Pia Kivisäkk, Albert M Anderson, Felicia C Chow, Kunling Wu, Raha M Dastgheyb, Leah H Rubin, Katherine Tassiopoulos, Robert A Parker, Emily P Hyle","doi":"10.1093/infdis/jiae623","DOIUrl":"https://doi.org/10.1093/infdis/jiae623","url":null,"abstract":"Background This study examined the relationship between neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and cognition in people living with HIV (PLWH) at baseline and over time. Methods Plasma and clinical data were available from PLWH aged ≥45 years with HIV RNA &amp;lt;200 copies/mL enrolled in the AIDS Clinical Trials Group HAILO cohort study. We measured plasma NfL and GFAP using a single molecule array platform. Four neuropsychological assessments, standardized to z-scores and averaged (NPZ-4), were used as a marker of cognitive function. Date of plasma collection marked study baseline; longitudinal changes in NPZ-4 were summarized by slope. Linear regressions between biomarkers and baseline NPZ-4 were adjusted for demographic factors. Regressions of longitudinal data were adjusted for baseline NPZ-4 and weighted by number of visits. Results The study included 503 participants with a median [IQR] age of 52 [48, 57] years, observation of 6 [5, 7] years, and 26% had baseline cognitive impairment defined by HAILO. Cross-sectionally, higher NfL (β=-0.76, p&amp;lt;0.01) and GFAP (β=-0.44, p=0.02) were associated with worse baseline NPZ-4. Longitudinally, the median [IQR] NPZ-4 slope was 0.003 [-0.06, 0.06] units/year with 48% demonstrating cognitive decline (slope&amp;lt;0). Higher NfL (β=-0.08, p&amp;lt;0.01), but not GFAP (β=-0.03, p=0.08), was associated with cognitive decline. Conclusions NfL and GFAP were associated with worse cognition cross-sectionally; only NfL was associated with longitudinal cognitive decline. However, the clinical utility of NfL and GFAP is uncertain given small effect sizes and should be studied in populations with more rapid decline (e.g., aged ≥60).","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"114 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pre-HIV α4β7hi CD4+ T cells and HIV risk among heterosexual individuals in Africa 非洲异性恋者HIV前α4β7hi CD4+ T细胞与HIV风险
Pub Date : 2024-12-25 DOI: 10.1093/infdis/jiae638
Tosin E Omole, Huong Mai Nguyen, Agata Marcinow, Myo Minn Oo, Naima Jahan, Aloysious Ssemaganda, Giulia Severini, Katherine K Thomas, Connie Celum, Nelly Mugo, Andrew Mujugira, James Kublin, Lawrence Corey, Aida Sivro, Jairam R Lingappa, Glenda Gray, Lyle R McKinnon
Background CD4+ T cells expressing α4β7 are optimal targets for HIV infections, with higher pre-HIV α4β7hi expression linked to increased HIV acquisition and progression in South African women. However, similar associations were not observed in men who have sex with men (MSM) or people who inject drugs (PWID) in the Americas, indicating need for further research. Methods This retrospective case-control study enrolled heterosexual men and women from South Africa (HIV Vaccine Trials Network; HVTN 503) and East Africa (Partners Pre-Exposure Prophylaxis/Couples’ Observational Study; PP/COS), quantifying α4β7 expression on CD4+ T cells as a predictor of subsequent HIV risk using flow cytometry analyses. Results Associations between α4β7hi expression and HIV acquisition varied across cohorts. In HVTN 503, women had a higher risk estimate compared to men, but this was not significant. In PP/COS, α4β7hi expression was generally protective, particularly in Ugandans. Additionally, α4β7hi expression inversely correlated with peak viral load in PP/COS but not in HVTN 503; in the latter cohort, α4β7hi expression was inversely correlated with the CD4/CD8 ratio and predicted rapid CD4+ T cell decline, similar to what was observed previously in South Africa. Conclusions These findings suggest that α4β7hi expression on CD4+ T cells may not predict HIV acquisition and progression in all contexts, which may be due to cohort effects, modes of transmission, viral clade, or other factors.
表达α4β7的CD4+ T细胞是HIV感染的最佳靶点,在南非妇女中,较高的HIV前期α4β7hi表达与HIV感染和进展增加有关。然而,在美洲的男男性行为者(MSM)或注射吸毒者(PWID)中没有观察到类似的关联,这表明需要进一步的研究。方法本回顾性病例对照研究纳入了来自南非的异性恋男性和女性(HIV Vaccine Trials Network;HVTN 503)和东非(伴侣接触前预防/夫妻观察性研究;PP/COS),利用流式细胞术分析定量α4β7在CD4+ T细胞上的表达,作为随后HIV风险的预测因子。结果α4β7hi表达与HIV感染的相关性在不同队列中存在差异。在HVTN 503中,女性的风险估计值高于男性,但这并不显著。在PP/COS中,α4β7hi的表达通常具有保护作用,尤其是在乌干达。此外,α4β7hi的表达与PP/COS的病毒峰值载量呈负相关,而在HVTN 503中无相关;在后一个队列中,α4β7hi的表达与CD4/CD8比率呈负相关,并预测CD4+ T细胞的快速下降,类似于之前在南非观察到的结果。结论CD4+ T细胞上α4β7hi的表达可能与队列效应、传播方式、病毒进化或其他因素有关,不能预测所有情况下HIV的获得和进展。
{"title":"Pre-HIV α4β7hi CD4+ T cells and HIV risk among heterosexual individuals in Africa","authors":"Tosin E Omole, Huong Mai Nguyen, Agata Marcinow, Myo Minn Oo, Naima Jahan, Aloysious Ssemaganda, Giulia Severini, Katherine K Thomas, Connie Celum, Nelly Mugo, Andrew Mujugira, James Kublin, Lawrence Corey, Aida Sivro, Jairam R Lingappa, Glenda Gray, Lyle R McKinnon","doi":"10.1093/infdis/jiae638","DOIUrl":"https://doi.org/10.1093/infdis/jiae638","url":null,"abstract":"Background CD4+ T cells expressing α4β7 are optimal targets for HIV infections, with higher pre-HIV α4β7hi expression linked to increased HIV acquisition and progression in South African women. However, similar associations were not observed in men who have sex with men (MSM) or people who inject drugs (PWID) in the Americas, indicating need for further research. Methods This retrospective case-control study enrolled heterosexual men and women from South Africa (HIV Vaccine Trials Network; HVTN 503) and East Africa (Partners Pre-Exposure Prophylaxis/Couples’ Observational Study; PP/COS), quantifying α4β7 expression on CD4+ T cells as a predictor of subsequent HIV risk using flow cytometry analyses. Results Associations between α4β7hi expression and HIV acquisition varied across cohorts. In HVTN 503, women had a higher risk estimate compared to men, but this was not significant. In PP/COS, α4β7hi expression was generally protective, particularly in Ugandans. Additionally, α4β7hi expression inversely correlated with peak viral load in PP/COS but not in HVTN 503; in the latter cohort, α4β7hi expression was inversely correlated with the CD4/CD8 ratio and predicted rapid CD4+ T cell decline, similar to what was observed previously in South Africa. Conclusions These findings suggest that α4β7hi expression on CD4+ T cells may not predict HIV acquisition and progression in all contexts, which may be due to cohort effects, modes of transmission, viral clade, or other factors.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Vector induced humoral responses after rVSVΔG-ZEBOV-GP immunization identify vaccinated individuals and correlate with Ebola virus glycoprotein antibodies 载体诱导的体液反应rVSVΔG-ZEBOV-GP免疫后确定接种疫苗的个体,并与埃博拉病毒糖蛋白抗体相关
Pub Date : 2024-12-24 DOI: 10.1093/infdis/jiae632
Prabha Chandrasekaran, Irina Maljkovic Berry, Viviane Callier, Scott M Anthony, Krystle Hensley, Jens H Kuhn, Kathryn Shaw-Saliba, Stephen B Kennedy, Mark Kieh, Sarah M Browne, Ian Crozier, Richard T Davey, H Clifford Lane, Lisa E Hensley, Dean A Follmann
Background The robustness and persistence of vaccine antigen-induced antibodies are often used as proxy indicators of vaccine efficacy, but immune responses to vaccine vectors are typically less well-defined. Our study considered the kinetics of immunoglobulin (IgG) responses against the vector (vesicular stomatitis Indiana virus [VSIV]) nucleoprotein (N) and the inserted antigen (Ebola virus [EBOV]) glycoprotein (GP1,2) components of the rVSVΔG-ZEBOV-GP (rVSV-ZEBOV) vaccine and evaluated their use as biomarkers to confirm self-reported vaccination status. Methods From the Partnership for Research on Ebola Virus in Liberia (PREVAIL) I clinical trial (NCT02344407), we randomly selected 212 participants who received rVSV-ZEBOV (n=107) or placebo (n=105). Levels of IgG antibodies to EBOV GP1,2 or VSIV N were measured using the Filovirus Animal Non-Clinical Group (FANG) ELISA and a newly developed single-molecule array (Simoa) immunoassay, respectively. Results Anti-EBOV GP1,2 IgG and anti-VSIV N IgG were first detected 10–14 d post-vaccination, further increased at 28 d, and remained stable through 360 d. Antibody titers were significantly higher in women compared to men. Anti-EBOV GP1,2 and anti-VSIV N IgG titers were significantly correlated (p&lt;0.001) at 28 d (r=0.47), 180 d (r=0.45), and 360 d (r=0.59). At 28 d, the area under the curve (AUC) of receiver operating characteristic (ROC) curves discriminated vaccinated from unvaccinated patients with high accuracy (AUC=0.965 for anti-VSIV N IgG; AUC=0.945 for anti-EBOV GP1,2 IgG [p&lt;0.001]). Conclusions We report a reliable assay to measure vector-induced humoral responses after rVSV-ZEBOV vaccination and demonstrate the assay’s utility to confirm vaccination status.
疫苗抗原诱导抗体的稳健性和持久性通常被用作疫苗效力的代理指标,但对疫苗载体的免疫反应通常不太明确。我们的研究考虑了免疫球蛋白(IgG)对载体(水疱性口炎印第安纳病毒[VSIV])核蛋白(N)和插入抗原(埃博拉病毒[EBOV])糖蛋白(GP1,2)成分rVSVΔG-ZEBOV-GP (rVSV-ZEBOV)疫苗的反应动力学,并评估了它们作为生物标志物的用途,以确认自我报告的疫苗接种状态。方法从利比里亚埃博拉病毒研究伙伴关系(PREVAIL) I临床试验(NCT02344407)中随机选择212名接受rVSV-ZEBOV (n=107)或安慰剂(n=105)的参与者。分别采用丝状病毒动物非临床组(FANG) ELISA和新开发的单分子阵列(Simoa)免疫分析法检测EBOV GP1、2或VSIV N的IgG抗体水平。结果接种后10 ~ 14 d首次检测到ebov抗体GP1、2 IgG和vsiv抗体N IgG,接种后28 d进一步升高,接种后360 d保持稳定,女性抗体滴度明显高于男性。抗ebov GP1,2和抗vsiv N IgG滴度在28 d (r=0.47), 180 d (r=0.45)和360 d (r=0.59)时显著相关(p<0.001)。28 d时,受试者工作特征曲线(ROC)曲线下面积(AUC)区分接种者与未接种者准确率较高(抗vsv N IgG AUC=0.965;抗ebov GP1,2 IgG的AUC=0.945 [p<0.001])。我们报告了一种可靠的方法来测量rVSV-ZEBOV疫苗接种后载体诱导的体液反应,并证明了该方法在确认疫苗接种状态方面的实用性。
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The Journal of Infectious Diseases
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