AMB  >> Vol. 8 No. 3 (September 2019)

    土拉弗朗西斯菌的研究现况
    Current Status of Research on Francisella tularensis

  • 全文下载: PDF(598KB)    PP.130-138   DOI: 10.12677/AMB.2019.83016  
  • 下载量: 41  浏览量: 75   国度天然迷信基金支撑

作者:  

苏 超:大年夜理大年夜学公共卫生学院,云南 大年夜理;云南省处所病防治所/云南省天然疫源性疾病防控技巧重点实验室/云南省鼠疫防治研究中间/徐建国院士任务站,云南 大年夜理;
吴鹤松,杨桂荣:云南省处所病防治所/云南省天然疫源性疾病防控技巧重点实验室/云南省鼠疫防治研究中间/徐建国院士任务站,云南 大年夜理;
宋志忠:云南省疾病预防控制中间,云南 昆明

关键词:
土拉热土拉弗朗西斯菌研究现况综述Tularemia Francisella tularensis Research Status Review

摘要:

土拉热,是由土拉弗朗西斯菌惹起的一种人兽共得病。该病最早于1919年由E. Francis在美国的土拉县发明,是以被定名为土拉热。我国在1959年的黑龙江省报导了第一路人世感染。因其致病性强、易于传播的特点,被美国CDC列为A类生物恐怖病原体,是以对本病的深刻研究具有重要的实际意义。本文从土拉弗氏菌的发明史、病原学特点、致病及传播机制、罕见检测办法、疾病的诊断、临床表示及治疗、疫苗研究等几个方面停止了综述。

Tularemia is a zoonotic disease caused by Francisella tularensis. The disease was first discovered in 1919 by E. Francis in Tulla County in the United States, so it was named Tularemia. In 1959, our country reported the first human infections in Heilongjiang province. Due to its characteristics of high pathogenicity and easy transmission, it is regarded as a class A bioterrorism pathogen by the CDC of the United States. Therefore, the in-depth study of this disease has important practical significance. In this paper, we reviewed the discovery history, pathogenic characteristics, pathogenic and transmission mechanism, common detection methods, disease diagnosis, clinical manifestations and treatment, vaccine research, etc.

1. 引言

土拉热,是由土拉弗朗西斯菌(简称土拉菌)经得病的野活泼物、带菌的剥削者豸和遭受细菌污染的水或食品等,所传播惹起的人兽共患热性感染疾病,由于最后主如果在野生啮齿类植物特别是野兔中风行,故又被称之为野兔热或兔热病,多产生于北半球国度 [1] [2]。常忽然起病,高热伴寒噤、淋趋承肿大年夜及毒血症症状,由于入侵门路较多、受累脏器轻重不一,故临床表示呈多样化。

2. 土拉菌的发明史

土拉热的发明,包含致病因子的分别、致病因子与人类疾病的接洽、组织病理学和风行病学的解释是美国的一项重要成就。1906年旧金山大年夜地动产生后,美国公共卫生所鼠疫实验室主任G. W. McCoy对灾区的地松鼠等鼠类的鼠疫病停止了细菌学查询拜访。在一些地松鼠的样本中,带有鼠疫病的典范变更,但试图分别病原体的测验测验掉败了。在试用了更有养分的培养基后,MCCOY和CHAPIN成功的分别出了一种新的微生物 [3] [4] [5] [6] [7],并以美国加利福尼亚州中部的土拉县这一最后发明它的处所定名为土拉菌。在人类病例中,该病原初次是在伴随部分淋趋承肿大年夜的结膜炎患者身上分别取得的 [8]。

1919年,E. Francis作为公共卫生官员从华盛顿特区被派往犹他州查询拜访鹿蝇热。随后从重症病人的血液平分别出了土拉菌,并对该疾病在鼠类、家兔和人类中的病理改变停止了广泛的研究,由于前期从人体血液中也分别到了这类病菌,是以这类疾病便被定名为了土拉热。Francis创造了基于培养和血清学的土拉热诊断办法,同时描述了实验室感染病例,从而将该病菌肯定为实验室风险病菌 [9] [10] [11]。而后工资了纪念E. Francis在研究土拉菌上的汗青成就,这类病菌便被正式改名为了Francisella tularensis (土拉弗朗西斯菌) [12]。

1925年,在E. Francis对土拉病停止深刻研究时代,Hachiro Ohara描述了日本的一种疾病,其临床表示与土拉病类似。后来Riki Ohara密斯自愿成为实验对象,她让Ohara用一只染病兔子的身材组织在本身左手背外面涂抹,Ohara密斯出现了典范的发热和淋趋承肿大年夜症状,并在淋趋承组织活检中,检出了细菌,随后被E. Francis肯定为F. tularensis [13]。

在我们国度,土拉菌的研究起步较晚,最早是于1957年从黄鼠的体内被分别取得的,而人世第一路土拉热病例是1959年在黑龙江省被报导的 [14]。随后新疆自治区、西藏自治区、甘肃省等地也被相继证明存在着土拉热的天然疫源地 [15] [16],并从这些地区的病人、序文节肢植物、啮齿植物等体内分别到了照应的病原体。在1986年,山东省的某个肉类加工厂内忽然爆发了人世疫情,共产生31个病例 [17]。以后,在我国有关土拉热的人世疫情及植物疫情情况均鲜为报导,不知能否由于生态情况变更所招致既往的疫源地消掉或处于静息状况,又或是由于人员、技巧等条件的限制而未能对此病展开相干的诊断及监测。别的值得留意的是,该病诸如宿主植物感染情况及种类、疫源分布情况及类型、菌体分子生物学差别等浩大风行病学成绩今朝还没有完全清楚,值得人们深刻思虑并展开相干的查询拜访研究 [18]。

3. 病原学特点

土拉菌是一种革兰氏阴性、过氧化氢酶阳性、多形性和非活动性的球杆菌,是细胞内兼性病原体,可在巨噬细胞、肝细胞和上皮细胞等不合类型的细胞内发展 [3] [19] [20] [21]。它须要半胱氨酸或胱氨酸的发展情况,在恰当的固体培养基(如含1%血红蛋白的胱氨痛心血琼脂培养基)上,培养2~4天后能构成明显的乳白色凸出菌落。能分化无限的碳水化合物,从而产酸,但不产气,并且不轻易与其他革兰氏阴性菌经过过程惯例诊断试剂盒停止辨别。其细胞壁具有异常程度高的脂肪酸,在该属中具有独特的特点,野生菌株具有丰富的脂质囊,但既没有毒性也没有免疫原性 [3] [22] [23],这些特点可以经过过程气液色谱法停止辨认 [24]。别的该细菌对外界天然情况有很强的抵抗才能,根据研究发明,其在泥土、水、外相、肉中可以存活数十天,在植物的尸首傍边乃至100余天仍能存活 [25]。

土拉菌有四个亚种:A型土拉热亚种(F. tularensis subsp. tularensis)、B型全北区亚种(F. tularensis subsp. holarctica)、中亚细亚亚种(F. tularensis subsp. mediaasiatica) 和新凶手亚种(F. tularensis subsp. novicida) [26] [27]。个中A型和B型可以惹起人类疾病,而subsp. mediaasiatica在人类中被认为是相对毒性较低的亚种,由于只要多数的已知病例是由该亚种惹起,subsp. novicida对人类根本无致病性 [28]。A型菌株重要分布于加拿大年夜和美国,而B型菌株简直遍及于包含欧洲在内的全部北半球 [29]。一切的亚种中 F. tularensis subsp. tularensis的毒力是最强的,有研究注解在缺乏照应治疗药物或抗菌素的情况下,十个菌量就有能够招致急性、乃至致命性的病情 [30],并且被其感染后病发率高达30%~60% [31]。基于这些特点,只需经过过程气溶胶门路被异常小的菌量感染既能够招致异常严重的病情乃至大年夜面积的风行,并且该菌曾被前苏联、美国和日本等国度作为生物战剂研究,是以极有能够被用作气溶胶生物化学兵器,是以被美国CDC作为经久展开“防生化恐怖”的重要监测目标,并被列为A类生物恐怖病原体 [32]。

4. 致病与传播机制

土拉菌的天然宿主序文重要为蜱、兔、鼠等节肢植物和哺乳类植物 [2]。

在欧洲,啮齿类哺乳植物和兔形目植物被认为是最重要的植物宿主 [33]。人类可经过过程接触受感染的哺乳植物、节肢植物或受污染的水或食品而传播 [34],例如直接接触被感染的植物感染(经过过程皮肤破损、划痕或组织毁伤)、经过过程吸血节肢植物(如跳蚤、虱子、蚊虫、臭虫、蚊子、扁虱)叮咬、经过过程饮用受污染的水、吃被污染的食品、或经过过程吸入带菌的尘埃 [35]。同时,也有实验室取得性土拉病的报导 [36]。

土拉菌侵入机体的一个明显的特点是可以或许经过过程几种门路引诱吞噬感化从而进入多种类型细胞,特别是巨噬细胞,并在巨噬细胞中敏捷逃离吞噬体,前去细胞质中大年夜量复制 [28] [37],经过过程吞噬体逃逸和胞质复制在吞噬细胞体内存活,终究招致炎性体激活和宿主细胞的逝世亡。是以,土拉菌的毒力源于它在受感染细胞,特别是巨噬细胞细胞质中大年夜量滋长的才能 [38]。这些滋长侵入过程须要弗朗西斯菌致病岛(FPI)的支撑,它编码了一种VI型渗出体系(T6SS),并在病菌感染细胞内时活泼,经过过程一种依附T6SS渗出的外膜脂蛋白IgIE,从而在土拉菌的致病过程当中起到重要的感化 [39]。别的,C3补体是人体中必须的一种疗养素,有研究发明它不只能明显增长巨噬细胞对Schu S4的摄取,并且能引诱巨噬细胞的逝世亡,在调理巨噬细胞活性方面,C3补体疗养感化对土拉菌的辨认起到了异常重要的感化 [40]。

近期有研究注解,瘦削同样成了感染土拉病的重要易感身分之一,由于瘦削个别基本瘦素表达的增长招致了持续低程度的炎症反响,使他们更轻易感染土拉菌,并增长了免疫病理细胞因子风暴的产生。 [41] 别的稀有据显示,外膜蛋白TolC在调理宿主免疫反响和土拉菌毒力方面也发挥了守旧和关键的感化,同时也强调了土拉菌病发机制中菌株和途径依附存在着必定的差别 [42]。

5. 经常使用的检测办法

土拉热作为一种天然疫源性人兽共患感染疾病,今朝在很多地区仍在风行,基于其可以通由气溶胶传播的特点,给防控治疗机构的考验剖断等任务带来了巨大年夜的艰苦。土拉菌的传统考验剖断办法重要有惯例分别培养 [1] 、酶联免疫吸附实验 [2] [43] 、微量血液凝集实验 [44] 、胶体金 [45] 、浅显PCR [46] [47] [48] [49] [50] 等。而今,伴随着迷信技巧的赓续生长和基本医学研究技巧的赓续进步,开辟出了浩大新的考验检测剖断办法,并被成功应用于包含土拉菌在内的微生物考验剖断过程傍边。例如荧光免疫技巧 [51] 、流式细胞技巧 [51] 、Real-time PCR [52] [53] [54] 、核酸杂交 [55] 、质谱分析 [56] [57] 、生物芯片 [58] 、生物传感器 [59] 、乳胶凝集实验 [60] 等,这些考验检测技巧在特异度和灵敏度方面都各具优势,特别是有的办法具有高通量和快速的长处,加倍合适于检测时间请求高、样本量较大年夜的任务,也为科研任务人员供给了加倍丰富的研究技巧手段 [61] [62]。

在分析剖断不合亚种间种群差别方面,比较功能基因组学对解释这些差别眼前的一些分子机制供给了很好的赞助。比如,设计一种用于检测弗朗西斯菌多个物种/亚转录本的共享探针微阵列,便可以或许停止比较转录分析,如许就可以够凹陷这些人类菌株相对病发机制中的关键差别,并且这类战略广泛的适应性,可以推行到其它亲缘关系较近菌种间的种间分析 [63]。

6. 土拉热的诊断、临床表示及治疗

根据世卫组织规定,确诊土拉病例须要分别培养,并经过过程抗原或DNA检测将培养物剖断为土拉菌。而临床诊断实验室现有的商用生化剖断体系不克不及精确剖断土拉菌。另外,具有配对血清标本滴度的四倍差别(试管或微量凝集实验)或ELISA有明显性差别(至少有一个血清阳性)也可确诊 [64]。由于土拉热的诊断较为艰苦,建议在有感染非典范微生物风险的患者中,在惯例治疗没有明显后果时,可以困惑为土拉热。精确的诊断须要高度确当心心思,并对这类异常挑剔的细菌停止经久的血液培养和检测。

人类的临床表示重要取决于感染门路,随着感染门路的不合,其症状表示和严重程度也各不雷同 [65]。但普通较为典范的症状是头痛、发热、腹泻和呼吸艰苦。表1描述了6种不合的典范临床表示情势 [66] [67],而菌血症的产生常常与潜伏的疾病有关,如糖尿病、高龄、酗酒或应用免疫克制剂等 [68],在血液培养平分别到土拉菌的情况是异常罕有的。

严重的土拉菌病须要住院治疗,其一线治疗药物是口服氨基糖苷类。与多西环素比拟,氨基糖苷类药物平日具有较低的最低抑菌浓度、杀菌后果和较低的治疗掉败率 [69]。在较轻的病例中,建议应用喹诺酮类药物、多西环素和氯霉素 [64] [70]。值得留意的是,土拉菌对包含碳青霉烯类在内的一切β-内酰胺类抗生素都具有耐药性 [71]。最新发明一种治疗酒精依附的药物二硫磺胺也能够克制土拉菌的体外发展,同时有研究注解该药物能够合适作为土拉热的体内治疗药物,但还需停止进一步的研究 [72]。

7. 疫苗研究

由于土拉菌是一种具有高度感染性的细菌,同时有能够被用作生物兵器,是以开辟一种有效的疫苗

Table 1. Common clinical types of Tula fever [66] [67]

表1. 土拉热的罕见临床类型 [66] [67]

是非常须要的 [73] [74] [75]。为了开辟一种能有效对抗土拉热的疫苗,人类测验测验采取了多种不合的战略。最早存在的土拉热疫苗是Lee Foshay于1930年临盆的一种灭活疫苗 [76]。研究发明,以已杀灭的土拉菌为基本的制剂对毒性菌株的感染仅能产生微弱的保护感化,这类疫苗在自愿者测试中被证明可以预防土拉菌的皮肤感染,但不克不及预防呼吸体系感染 [77] [78]。以后在前苏联,Gaiskii和El’bert成功地将一株天然分别的土拉菌减毒成一种安然有效的疫苗株,并于1946年在苏联停止了大年夜范围疫苗接种 [79] [80]。

1956年,一支含有活疫苗菌的安瓿早年苏联莫斯科的加玛利亚研究所,被转移到美国马里兰州德特里克堡的美国陆军感染病医学研究所。该研究所经过过程对植物模型的研究,选择了两种菌落变体中的一种,并对其停止人体安然性和有效性测试 [81] [82],将其定名为F. tularensis活疫苗株(LVS),用于高危人员的疫苗接种。LVS在自愿者测试中被不雅察到其对tularensis A型毒株的感染可以或许起到部分保护感化 [83]。自从1960年德特里克堡引入LVS疫苗后,该地区高危人员的呼吸性土拉病病发率由5.7‰降至了0.27‰ [84],溃疡腺型土拉病人虽然症状和体征有所减轻,然则其病发率保持不变。遗憾的是,该活疫苗株未在美国或其他国度取得正式许可,是以清除公共应用的能够,只能在研究中部分应用,其重要缘由照样关于该细菌衰减源的不肯定性和培养中的不稳定性 [81] [85] [86],在将来该疫苗可否大年夜范围商用异样充斥着浩大的不肯定性 [32]。是以,研究一种新型的土拉热疫苗一向是近年来迷信界的一个重要目标,终究欲望可以或许开辟出一种具有完全保护性的减毒疫苗,从而清除或进一步增添人们对疫苗安然性的担心。

今朝曾经从LVS和剧毒的Schu S4菌株中衍生出很多减毒活突变体 [86] [87],这些新的候选疫苗已在植物模型中显示出不合程度的效力,个中一些正在进一步开辟并应用于人类。例如:有研究注解ΔpdpC能够作为一个候选疫苗,由于其研究数据注解其是一个安然并可致兔热病免疫的候选疫苗,合适进一步的临床开辟 [88]。别的也有研究发明,应用转基因O抗原的糖结合疫苗可引诱机体产生对土拉菌的保护性抗体,并且这类抗体能更好的辨认那些与机体有更高亲和力的HMW和VHMW抗原上表达的长度依附表位 [89]。

8. 研究展望

土拉菌的致病才能强,其气溶胶形状极易大年夜面积广泛传播,是重要的生物恐怖病原体。然则由于我国研究起步较晚,外乡重要菌种毒力较弱,招致人们对其熟悉不多,看重程度不敷。

根据我国今朝的研究,根本认为该病仅存在于我国的南方地区 [62],然则我国地形、气候、物种多样性各省各地区均存在很大年夜差别,例如云南省根本具有从热带到亚热带、热带的各类气候、海拔类型,动植物物种丰富,被称为动植物王国。而很多南边地区对该疾病并未展开过体系周全的查询拜访,疾病分布情况其实其实不明白,是以很有须要在南边地区展开体系的查询拜访研究,以明白该病在我国的详细分布情况。

固然今朝关于土拉菌的浩大成绩还存在着盲区,然则荣幸的是,随着以后分子生物学等技巧的快速生长,为我们的研究供给了加倍有力的对象与办法。例如关于土拉菌的毒力与疫苗的研究曾经成为当下的热点,并且疫苗的研究有很好的应用前景,特别是作为一种“战备品”用以应对突发的挑衅具有巨大年夜的计谋意义。别的,比较功能基因组学也为土拉菌的研究供给了新的偏向。

基金项目

本文章为国度天然迷信基金项目,基金号:81560545。

NOTES

*通信作者。

文章援用:
苏超, 吴鹤松, 杨桂荣, 宋志忠. 土拉弗朗西斯菌的研究现况[J]. 微生物前沿, 2019, 8(3): 130-138. https://doi.org/10.12677/AMB.2019.83016

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