Vectors

向量
  • 文章类型: Journal Article
    目的:跳蚤Ctenocephalidesfelis(Siphonaptera:Pulicidae),在全球范围内寄生狗和猫,作为影响动物和人类的各种病原体的媒介。对环保的兴趣日益浓厚,植物性产品促使这项研究。该研究的目的是确定来自网状Copaifera的精油(EO)的化学成分,柑橘,Lavandulahybrida和Salviasclarea,评估它们的杀虫和驱虫特性,确定致死浓度(LC50和LC90),并评价其体外对Ctenocephalidesfelis的残留疗效。
    方法:具有火焰离子化检测器的气相色谱法分析EO组成。体外试验涉及制备各种浓度的EO溶液。每个生命阶段的十个标本(鸡蛋,幼虫,蛹,成年)用于杀虫活性评估。使用10cm2滤纸条评估杀虫活性,每个用0.200mL的测试溶液处理。使用相同滤纸的23.76cm2圆盘评估未成熟阶段的活动,每个用0.470mL的测试溶液处理。死亡率百分比使用(死亡昆虫数X100)/孵育昆虫数计算。Probit分析以95%置信区间计算LC50值。
    结果:主要的EO成分是β-石竹烯(EOCR),芳樟醇(EOLH),醋酸纤维素(EOSS),和柠檬烯(EOCP)。获得所有阶段的LC50值,除了巴拉迪氏梭菌的精油。所有的油在800μg/cm2时显示出驱避活性。OECR表现出更大的残余功效。
    结论:每种EO对特定的C.felisfelis阶段表现出优异的杀虫活性。
    OBJECTIVE: The flea Ctenocephalides felis (Siphonaptera: Pulicidae), parasitizes dogs and cats globally, acting as a vector for various pathogens affecting both animals and humans. Growing interest in environmentally friendly, plant-based products prompted this study. The aim of the study was to determine the chemical composition of essential oils (EOs) from Copaifera reticulata, Citrus paradisi, Lavandula hybrida and Salvia sclarea, assessing their insecticidal and repellent properties, determining lethal concentrations (LC50 and LC90), and evaluating residual efficacy in vitro against Ctenocephalides felis felis.
    METHODS: Gas Chromatography with Flame Ionization Detector analyzed EO composition. In vitro tests involved preparing EO solutions at various concentrations. Ten specimens from each life stage (egg, larva, pupa, adult) were used for insecticidal activity assessment. Adulticidal activity was assessed using 10 cm2 filter paper strip, each treated with 0.200 mL of the test solution. Immature stages activities were evaluated using 23.76 cm2 discs of the same filter paper, each treated with 0.470 mL of the test solution. Mortality percentage was calculated using (number of dead insects × 100) / number of incubated insects. Probit analysis calculated LC50 values with a 95% confidence interval.
    RESULTS: Major EO constituents were β-caryophyllene (EOCR), linalool (EOLH), linalyl acetate (EOSS), and limonene (EOCP). LC50 values were obtained for all stages except for the essential oil of C. paradisi. All oils showed repellent activity at 800 μg/cm2. OECR exhibited greater residual efficacy.
    CONCLUSIONS: Each EO demonstrated superior insecticidal activity against specific C. felis felis stages.
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  • 文章类型: Journal Article
    这是特刊“合并生态和控制媒介作为降低人畜共患病风险的策略:特刊导论”的介绍性论文。
    This is the introductory paper to the special issue \"Merging ecology and control of vectors as a strategy to reduce zoonotic risks: an introduction to the Special Issue\".
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  • 文章类型: Journal Article
    腺病毒是无包膜DNA病毒,可引起多种症状,从轻度感染到各种宿主中威胁生命的疾病。由于这些病毒的独特特性,它们也已成为基因转移和癌症治疗工具的载体。腺病毒载体可通过修饰野生型病毒使其具有复制缺陷而用于基因治疗。这使得可以将特定的病毒基因换成携带治疗基因的区段,并将所得载体用作将基因递送至特定组织的手段。在这次审查中,我们概述了腺病毒载体的逐步发展,探索他们的特点,遗传修饰,以及在临床和临床前环境中的使用范围。一个重要的重点是他们在推进基因治疗中的关键作用,癌症治疗,免疫疗法,以及各种疾病疫苗开发的最新突破。
    Adenoviruses are non-enveloped DNA viruses that cause a wide range of symptoms, from mild infections to life-threatening diseases in a broad range of hosts. Due to the unique characteristics of these viruses, they have also become a vehicle for gene-transfer and cancer therapeutic instruments. Adenovirus vectors can be used in gene therapy by modifying wild-type viruses to render them replication-defective. This makes it possible to swap out particular viral genes for segments that carry therapeutic genes and to employ the resultant vector as a means of delivering genes to specified tissues. In this review, we outline the progressive development of adenovirus vectors, exploring their characteristics, genetic modifications, and range of uses in clinical and preclinical settings. A significant emphasis is placed on their crucial role in advancing gene therapy, cancer therapy, immunotherapy, and the latest breakthroughs in vaccine development for various diseases.
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  • 文章类型: Journal Article
    本次审查的目的是更新有关斯里兰卡主要疟疾病媒及其生物生态学和杀虫剂抗性状况的最新知识。相关数据是通过使用PubMed等数据库进行的全面文献检索收集的,NIH,谷歌学者和WebofScience。斯里兰卡几个世纪以来一直是疟疾的地方病。然而,由于协调一致的公共卫生努力,2012年报告了最后一例土著疟疾病例,2016年宣布该岛国无疟疾。尽管到目前为止,岛上已经报道了25只按蚊,只有按蚊和An。subpictus已分别被确定为疟疾的主要和次要媒介。两种媒介物种都作为物种复合体存在,每个复合体的兄弟物种的生物生态学和对疟疾寄生虫和杀虫剂的敏感性都不同。本文提供了有关疟疾媒介的生物生态学和杀虫剂抗性的全面和最新的说明,并强调了保持无疟疾状态之前的挑战。
    The objective of this review was to update the current knowledge on major malaria vectors in Sri Lanka and their bio-ecology and insecticide resistance status. Relevant data were collected through a comprehensive literature search performed using databases such as PubMed, NIH, Google Scholar and Web of Science. Sri Lanka had been endemic to malaria for centuries. However, due to a coordinated public health effort last indigenous malaria case was reported in 2012 and the island nation was declared free of malaria in 2016. Although 25 anopheline mosquitoes have been reported so far on the island, only Anopheles culicifacies and An. subpictus have been established as primary and secondary vectors of malaria respectively. Both vector species exist as a species complex, and the sibling species of each complex differ in their bio-ecology and susceptibility to malaria parasites and insecticides. The article provides a comprehensive and updated account of the bio-ecology and insecticide resistance of malaria vectors and highlights the challenges ahead of retaining a malaria-free status.
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  • 文章类型: Systematic Review
    背景:皮肤利什曼病(CL)在撒哈拉以南非洲的研究不足。CL的流行病学取决于其传播所涉及的物种。我们的目标是系统地审查有关利什曼原虫物种的可用数据,以及在撒哈拉以南非洲发生人类CL病例的媒介和水库,并讨论对病例管理和未来研究的启示。
    方法:我们系统地搜索了PubMed,Scopus,Cochrane和非洲指数Medicus。没有语言或发布日期的限制。审查是根据PRISMA指南进行的,并在PROSPERO(CRD42022384157)上注册。
    结果:总计,包括188项已发表的研究和37项来自灰色文献的报告。观察到上升趋势,45.7%的研究在2010年之后发表。东非(55.1%)的出版物数量远远超过西非(33.3%)。在东非,热带利什曼原虫水库的鉴定尚不清楚。这个物种也代表了治疗挑战,因为它通常对葡甲胺锑酸盐有抗性。在苏丹,多诺瓦尼利什曼原虫和严格的皮肤物种之间的杂种的存在可能导致重要的流行病学变化。在加纳,最近出现的CL可能涉及利什曼原虫亚属Mundinia的稀有物种。主要利什曼原虫的传播区域可能会扩大到萨赫勒地区以外,森林地区有分散的报道。虽然在西非干旱地区,主要的Phlebotomusduboscqi-啮齿动物复合体可能不是唯一的周期,应该澄清狗作为本分区域皮肤嗜性利什曼原虫物种的潜在水库的作用。锑酸盐葡胺是最常见的治疗方法,但物理方法和全身性药物如酮康唑和甲硝唑也被用于治疗L.
    结论:尽管最近关于该主题的研究数量有所增加,重要的是需要进行交叉研究,以进一步破译人类CL病例中涉及的利什曼原虫物种以及相应的媒介和储层,和影响传输动力学的环境因素。撒哈拉以南非洲分子生物学的发展有助于利用诊断和研究能力,并通过个性化治疗策略改善人类病例的管理。
    BACKGROUND: Cutaneous leishmaniasis (CL) is understudied in sub-Saharan Africa. The epidemiology of CL is determined by the species involved in its transmission. Our objectives were to systematically review available data on the species of Leishmania, along with vectors and reservoirs involved in the occurrence of human cases of CL in sub-Saharan Africa, and to discuss implications for case management and future research.
    METHODS: We systematically searched PubMed, Scopus, Cochrane and African Index Medicus. There was no restriction on language or date of publication. The review was conducted according to PRISMA guidelines and was registered on PROSPERO (CRD42022384157).
    RESULTS: In total, 188 published studies and 37 reports from the grey literature were included. An upward trend was observed, with 45.7% of studies published after 2010. East Africa (55.1%) represented a much greater number of publications than West Africa (33.3%). In East Africa, the identification of reservoirs for Leishmania tropica remains unclear. This species also represents a therapeutic challenge, as it is often resistant to meglumine antimoniate. In Sudan, the presence of hybrids between Leishmania donovani and strictly cutaneous species could lead to important epidemiological changes. In Ghana, the emergence of CL in the recent past could involve rare species belonging to the Leishmania subgenus Mundinia. The area of transmission of Leishmania major could expand beyond the Sahelian zone, with scattered reports in forested areas. While the L. major-Phlebotomus duboscqi-rodent complex may not be the only cycle in the dry areas of West Africa, the role of dogs as a potential reservoir for Leishmania species with cutaneous tropism in this subregion should be clarified. Meglumine antimoniate was the most frequently reported treatment, but physical methods and systemic agents such as ketoconazole and metronidazole were also used empirically to treat L. major infections.
    CONCLUSIONS: Though the number of studies on the topic has increased recently, there is an important need for intersectional research to further decipher the Leishmania species involved in human cases of CL as well as the corresponding vectors and reservoirs, and environmental factors that impact transmission dynamics. The development of molecular biology in sub-Saharan Africa could help in leveraging diagnostic and research capacities and improving the management of human cases through personalized treatment strategies.
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  • 文章类型: Journal Article
    本研究的主要目的是调查内脏利什曼病病媒的情况,重点关注它们在伊朗和其他一些旧世界国家的分布和与该疾病的关系。
    术语“伊朗与旧世界”随着关键词沙蝇,向量,内脏利什曼病,分布,还有血球病,在1930年至2018年的电子数据库中搜索,包括Pub-Med,WebofScience,谷歌学者,和MEDLINE。
    根据调查结果,Bobbi是一种山地物种,但它也被发现在平原,啮齿动物巢,和岩石裂缝。该物种被认为是伊朗内脏利什曼病的媒介之一。在阿富汗,伊朗,黎巴嫩,土耳其和格鲁吉亚。在伊朗,第一次感染黄体肿病和Ph.据报道,伊朗西北部有利什曼原虫病。大黄鱼是复杂的沙蝇之一,其成员包括Ph.少校(印度,尼泊尔,和巴基斯坦),Ph.neglectus(南欧,克里米亚和伊朗),Ph.叙利亚(西南亚,高加索),Ph.notus(阿富汗和伊朗),Ph.Wenyoni(伊朗和伊拉克),和Ph。wui(中国)。第一次自然感染Ph.2006年在法尔斯省内脏利什曼病的地方性病灶中报告了患有婴儿利什曼病的alexandri,伊朗南部。
    该项目的发现表明,拉鲁西索亚属的沙蝇物种在伊朗所有类型的内脏利什曼病的传播中起着关键作用。
    UNASSIGNED: This study\'s major aim is to investigate the situation of visceral leishmaniasis vectors, with a focus on their distribution and relationships to the disease in Iran and some other old-world nations.
    UNASSIGNED: The terms Iran and the Old World, along with the keywords sand flies, vectors, visceral leishmaniasis, distribution, and Phlebotomus, were searched in electronic databases from 1930 to 2018, including Pub-Med, Web of Science, Google Scholar, and MEDLINE.
    UNASSIGNED: According to the findings, Phlebotomus tobbi was a mountain species, but it was also found in the plains, rodent nests, and rock crevices. This species was considered to be one of the vectors of visceral leishmaniasis in Iran. Phlebotomus kandelakii has been caught in Afghanistan, Iran, Lebanon, Turkey and Georgia. In Iran, the first infection of Phlebotomus kandelakii and Ph. perfiliewi transcaucasicus with Leishmania infantum were reported in northwest of Iran. Phlebotomus major was one of the complex sand flies, and its members include Ph. major (India, Nepal, and Pakistan), Ph. neglectus (Southern Europe, Crimea and Iran), Ph. syriacus (Southwest Asia, Caucasus), Ph. notus (Afghanistan and Iran), Ph. wenyoni (Iran and Iraq), and Ph. wui (China). The first natural infection of Ph. alexandri with Leishmania infantum was reported in 2006 in endemic foci of visceral leishmaniasis in Fars Province, southern Iran.
    UNASSIGNED: The findings of this project suggest that sand fly species of the subgenus Larrousisus play a key role in the transmission of all types of visceral leishmaniasis in Iran.
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  • 文章类型: Journal Article
    蚊子可以将几种致病病毒传播给人类,但是它们的天然病毒群落也由无数其他病毒组成,例如昆虫特异性病毒(ISV)和感染共生微生物的病毒。除了越来越多的调查蚊子病毒的研究,大多数集中在少数城市物种上,人们对sylvatic蚊子的病毒体知之甚少,特别是在高生物多样性的生物群落中,如巴西生物群落。这里,我们使用metatracscriptometic方法,在巴西东北部的sylvatic-城市界面上,对来自大西洋森林的10种sylvatic蚊子物种的RNA病毒进行了表征。共检测到16个病毒家族。14个病毒家族的系统发育重建显示大多数序列是推定的ISV。系统发育定位和,在大多数情况下,与其他已知病毒的高RNA依赖性RNA聚合酶氨基酸差异的相关性表明,本文表征的病毒代表至少34种新病毒.因此,sylvatic蚊子病毒群落主要由高度不同的病毒组成,突出了我们对蚊子的自然病毒传播的知识仍然有限。此外,我们发现回收的病毒没有一个是在被调查的物种之间共享的,只有一个人与在秘鲁取样的蚊子中检测到的病毒有很高的同一性,南美洲。这些发现进一步深入了解了自然环境中蚊子和病毒之间的相互作用和共同进化。
    目的:蚊子是医学上重要的昆虫,因为它们在血液喂养过程中向人类和动物传播致病性病毒。然而,它们的天然微生物群也由一组不同的病毒组成,这些病毒不会对昆虫和其他宿主造成伤害,如昆虫特异性病毒。在这项研究中,我们使用无偏倚的转移基因组测序和深入的生物信息学方法对来自巴西东北部的热带蚊子的RNA病毒进行了表征。我们的分析显示,这些蚊子物种藏有各种各样的高度不同的病毒,大多数包括新的病毒物种。我们的发现揭示了许多新的病毒谱系,这首次扩大了我们对蚊子和病毒之间自然相互作用的理解。最后,它还提供了几个完整的基因组,值得进一步评估蚊子和脊椎动物宿主的致病性及其对致病性虫媒病毒的潜在干扰。
    Mosquitoes can transmit several pathogenic viruses to humans, but their natural viral community is also composed of a myriad of other viruses such as insect-specific viruses (ISVs) and those that infect symbiotic microorganisms. Besides a growing number of studies investigating the mosquito virome, the majority are focused on few urban species, and relatively little is known about the virome of sylvatic mosquitoes, particularly in high biodiverse biomes such as the Brazilian biomes. Here, we characterized the RNA virome of 10 sylvatic mosquito species from Atlantic forest remains at a sylvatic-urban interface in Northeast Brazil employing a metatranscriptomic approach. A total of 16 viral families were detected. The phylogenetic reconstructions of 14 viral families revealed that the majority of the sequences are putative ISVs. The phylogenetic positioning and, in most cases, the association with a high RNA-dependent RNA polymerase amino acid divergence from other known viruses suggests that the viruses characterized here represent at least 34 new viral species. Therefore, the sylvatic mosquito viral community is predominantly composed of highly divergent viruses highlighting the limited knowledge we still have about the natural virome of mosquitoes in general. Moreover, we found that none of the viruses recovered were shared between the species investigated, and only one showed high identity to a virus detected in a mosquito sampled in Peru, South America. These findings add further in-depth understanding about the interactions and coevolution between mosquitoes and viruses in natural environments.
    OBJECTIVE: Mosquitoes are medically important insects as they transmit pathogenic viruses to humans and animals during blood feeding. However, their natural microbiota is also composed of a diverse set of viruses that cause no harm to the insect and other hosts, such as insect-specific viruses. In this study, we characterized the RNA virome of sylvatic mosquitoes from Northeast Brazil using unbiased metatranscriptomic sequencing and in-depth bioinformatic approaches. Our analysis revealed that these mosquitoes species harbor a diverse set of highly divergent viruses, and the majority comprises new viral species. Our findings revealed many new virus lineages characterized for the first time broadening our understanding about the natural interaction between mosquitoes and viruses. Finally, it also provided several complete genomes that warrant further assessment for mosquito and vertebrate host pathogenicity and their potential interference with pathogenic arboviruses.
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  • 文章类型: Journal Article
    利什曼病是由利什曼原虫属原生动物引起的一组疾病,由咬伤的雌性沙蝇传播。当前工作的特征是在两个区域进行描述性研究:位于里约热内卢的ParqueEstadualdoRioDoce的森林区域,和另一个位于蒂莫泰奥-MG市的市区,目的是确定利什曼原虫的存在。和收集的雌性沙蝇的血液来源。部分雌性是从ParqueEstadualdoRioDoce获得的,部分是使用分布在提莫泰奥住宅中的19个集格特陷阱收集的。用于利什曼原虫的分子研究。DNA,使用ITS1基因,在寻找血源的过程中,使用CytB基因并对阳性样本进行测序.研究表明,在研究区域中至少有三种利什曼原虫:利什曼原虫(Viannia)braziliensis,亚马逊利什曼原虫(Leishmania),和利什曼尼亚(V.)古人类。白睡虫是蒂莫泰奥市区的主要沙蝇物种,对巴西利什曼原虫DNA的存在具有阳性诊断。我们在沙蝇中发现了来自Gallusgallus(鸡)和Susscrofa(猪)的血液。本研究表明,巴西利什曼原虫是研究区皮肤利什曼病的主要病因,在白睡虫作为媒介的有效参与下,以及Gallusgallus和Susscrofa作为雌性沙蝇的食物来源,并帮助维持沙飞的生命。
    Leishmaniasis is a group of diseases caused by protozoa of the genus Leishmania and is transmitted by the bite female sand fly. The present work is characterized as a descriptive study in two areas: a forest area located in the Parque Estadual do Rio Doce, and another urban area located in the municipality of Timóteo-MG, with the objective of identifying the presence of Leishmania spp. and the blood source of the collected female sand flies. Part of the females were obtained from the Parque Estadual do Rio Doce, and part was collected using 19 ligth traps distributed in residences of Timóteo. For molecular studies of Leishmania spp. DNA, the ITS1 gene was used, and in the search for blood source, the CytB gene was used and positive samples were sequenced. The study demonstrated that there are at least three species of Leishmania circulating in the study areas: Leishmania (Viannia) braziliensis, Leishmania (Leishmania) amazonensis, and Leishmania (V.) guyanensis. Nyssomyia whitmani was the predominant sand fly species in the urban area of Timóteo with a positive diagnosis for the presence of Leishmania braziliensis DNA. We found the presence of blood from Gallus gallus (Chicken) and Sus scrofa (Pig) in sand flies. The present study demonstrates that Leishmania braziliensis is the main agent of cutaneous leishmaniasis in the study area, with the effective participation of Nyssomyia whitmani as the vector and both Gallus gallus and Sus scrofa acting as a food source for female sand flies, and helping maintaining the sand fly life.
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  • 文章类型: Journal Article
    疟疾仍然是一个全球性的公共卫生问题,尽管它已经从许多国家消除。斯里兰卡和中国是最近获得消除疟疾地位的两个国家,东南亚的许多国家目前正在筹备到2030年实现同样的目标。然而,诺氏疟原虫,一种非人类灵长类疟疾寄生虫继续对该地区的公众健康构成威胁,感染了除东帝汶以外的东南亚所有国家的许多人。此外,其他非人灵长类疟疾寄生虫,如食蟹性疟原虫和疟原虫感染该地区的人类。非人灵长类动物,携带这些寄生虫的长尾和猪尾猕猴现在在村庄附近的农场和森林边缘越来越普遍。此外,这些地区也存在属于Lecuosphhyrus组的按蚊,这使得它们非常适合传播非人灵长类疟疾寄生虫。随着景观的变化和森林的砍伐,随着人类疟疾的消除,非人灵长类疟疾寄生虫将在未来几年影响更多的人类。也许是因为失去了豁免权,更多的人将被感染,目前在马来西亚被证明。因此,需要迅速采取控制措施,以在2030年之前实现消除疟疾的状态。然而,寄生虫的人畜共患起源和媒介行为对早期叮咬的变化似乎是该地区消除疟疾努力的绊脚石。在这次审查中,我们讨论了由于森林砍伐而消除疟疾所面临的挑战以及非人类灵长类动物疟疾寄生虫构成的严重威胁。
    Malaria continues to be a global public health problem although it has been eliminated from many countries. Sri Lanka and China are two countries that recently achieved malaria elimination status, and many countries in Southeast Asia are currently in the pipeline for achieving the same goal by 2030. However, Plasmodium knowlesi, a non-human primate malaria parasite continues to pose a threat to public health in this region, infecting many humans in all countries in Southeast Asia except for Timor-Leste. Besides, other non-human primate malaria parasite such as Plasmodium cynomolgi and Plasmodium inui are infecting humans in the region. The non-human primates, the long-tailed and pig-tailed macaques which harbour these parasites are now increasingly prevalent in farms and forest fringes close by to the villages. Additionally, the Anopheles mosquitoes belonging to the Lecuosphyrus Group are also present in these areas which makes them ideal for transmitting the non-human primate malaria parasites. With changing landscape and deforestation, non-human primate malaria parasites will affect more humans in the coming years with the elimination of human malaria. Perhaps due to loss of immunity, more humans will be infected as currently being demonstrated in Malaysia. Thus, control measures need to be instituted rapidly to achieve the malaria elimination status by 2030. However, the zoonotic origin of the parasite and the changes of the vectors behaviour to early biting seems to be the stumbling block to the malaria elimination efforts in this region. In this review, we discuss the challenges faced in malaria elimination due to deforestation and the serious threat posed by non-human primate malaria parasites.
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  • 文章类型: Journal Article
    基于腺相关病毒(AAV)的病毒载体广泛用于人类基因疗法,并且形成了几种遗传疾病的批准治疗的基础。对载体和转基因产品的免疫反应,然而,在临床实践中这些应用相当复杂。AAV载体的先天免疫识别的作用最初是不清楚的,鉴于动物模型中载体给药后早期的炎症反应通常是温和的,包括NHP研究。然而,最近的研究继续鉴定由AAV载体触发的并且用于为抗原呈递细胞提供激活信号和启动适应性免疫应答的先天免疫途径。通过内体DNA受体toll样受体9(TLR9)感知AAV基因组促进早期炎症反应和干扰素表达。因此,在浆细胞样树突状细胞(pDC)中TLR9>MyD88途径的激活导致通过I型干扰素(IFNI)和最终的CD8T细胞激活来调节抗原交叉呈递DC。或者,pDC还可以通过IL-1细胞因子的产生以TLR9非依赖性方式促进CD8+T细胞应答,从而激活IL-1R1>MyD88信号通路。AAV可以诱导单核细胞来源的DC中的细胞因子表达,这反过来又增加了抗体的形成。AAV衣壳与补体组分的结合可能进一步提高B细胞活化。在人类的高全身载体剂量下,AAV载体可以触发补体激活,通过经典和替代途径的贡献,导致严重的毒性。最后,已经提出了通过衣壳激活TLR2和核酸的其他先天受体的证据。这些观察结果表明,AAV载体可以启动几个并且可能冗余的先天性免疫途径,导致夸大的适应性免疫应答。
    Adeno-associated virus (AAV) based viral vectors are widely used in human gene therapy and form the basis of approved treatments for several genetic diseases. Immune responses to vector and transgene products, however, substantially complicate these applications in clinical practice. The role of innate immune recognition of AAV vectors was initially unclear, given that inflammatory responses early after vector administration were typically mild in animal models. However, more recent research continues to identify innate immune pathways that are triggered by AAV vectors and that serve to provide activation signals for antigen-presenting cells and initiation of adaptive immune responses. Sensing of the AAV genome by the endosomal DNA receptor toll-like receptor 9 (TLR9) promotes early inflammatory response and interferon expression. Thus, activation of the TLR9>MyD88 pathway in plasmacytoid dendritic cells (pDCs) leads to the conditioning of antigen cross-presenting DCs through type I interferon (IFN-I) and ultimately CD8+ T cell activation. Alternatively, pDCs may also promote CD8+ T cell responses in a TLR9-independent manner by the production of IL-1 cytokines, thereby activating the IL-1R1>MyD88 signaling pathway. AAV can induce cytokine expression in monocyte-derived DCs, which in turn increases antibody formation. Binding of AAV capsid to complement components likely further elevates B cell activation. At high systemic vector doses in humans and in non-human primates, AAV vectors can trigger complement activation, with contributions by classical and alternative pathways, leading to severe toxicities. Finally, evidence for activation of TLR2 by the capsid and of additional innate receptors for nucleic acids has been presented. These observations show that AAV vectors can initiate several and likely redundant innate immune pathways resulting in an exaggerated adaptive immune response.
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