Vibrio cholerae non-O1/O139：Epidemic, virulence factors and drug resistance
LI Feng-juan, KAN Biao, WANG Duo-chun
State Key Laboratory for Communicable Disease Prevention and Control, Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
Abstract
Diarrhea caused by Vibrio cholerae non-O1/O139 occurs frequently in many developing countries, several serogroups are involved the epidemic. In some places, the incidence of diarrhea caused by V. cholerae non-O1/O139 was even higher than that of O1 and O139 serogroups. It is believed that several virulence factors play the important roles in the pathogenicity of V. cholerae non-O1/O139, including enterotoxin, protease, hemolysin and the type three secretion system (TTSS), et al, but its pathogenic mechanism is very complicated and still not fully understood. Meanwhile, drug resistant and even multidrug resistant strains have emerged. This paper summarizes the research progress in the epidemic of diarrhea caused by V. cholerae non-O1/O139, its virulence factors and drug resistance.
非O1/O139群霍乱弧菌：流行、致病因子和耐药
李凤娟, 阚飙, 王多春
中国疾病预防控制中心传染病预防控制所, 传染病预防控制国家重点实验室, 北京 102206
收稿日期：2013-10-12
基金项目：国家自然科学基金（No.30872260）；国家科技重大专项（No.2008ZX10004-012）；传染病预防控制国家重点实验室 （No.2011SKLID201）
通讯作者：王多春，Tel：010-58900744，Email：wangduochun@icdc.cn
摘要
非O1/O139群霍乱弧菌引起的腹泻在许多发展中国家都有发生，其流行涉及到多个血清群。在有些地方，非O1/O139群霍乱弧菌腹泻的发病率甚至超过了O1/O139群霍乱弧菌腹泻的发病率。非O1/O139群霍乱弧菌的致病因子多种多样，肠毒素、蛋白酶、溶血素和三型分泌系统等被认为是重要的致病因子，但其致病机制非常复杂，至今仍然不完全清楚。随着抗生素使用的增加，出现了许多耐药甚至多重耐药菌株。本研究从非O1/O139群霍乱弧菌腹泻的流行情况、致病因子以及耐药方面加以综述。
非O1/O139群霍乱弧菌是指除O1和O139群霍乱弧菌以外的其他血清群的霍乱弧菌[1]。非O1/O139群霍乱弧菌广泛存在于环境中，尤其是水体和海产品中，是引起急性腹泻的主要病原菌之一，临床表现为轻症胃肠炎或严重的腹泻。非O1/O139群霍乱弧菌引起的腹泻在世界各地都时有发生。霍乱毒素(CT)和毒素共调菌毛(TCP)是O1和O139 群霍乱弧菌的主要毒力因子，但非O1/O139群 霍乱弧菌通常缺少CT和TCP。肠毒素(ST)、蛋白酶(Protease)、溶血素(HlyA)和三型分泌系统(TTSS)是非O1/O139群霍乱弧菌重要的致病因子。同时，也出现了许多耐药和多重耐药菌株。由于非O1/O139群霍乱弧菌引起的腹泻通常不像O1/O139群那么剧烈，往往导致人们忽略其危害的严重性。本研究基于近几年来的文献报道，从非O1/O139群霍乱弧菌腹泻的流行情况、致病因子以及耐药方面加以综述。
1 流行情况
在许多发展中国家，尤其是亚洲或是南美等一些经济及卫生条件比较落后的地方，几乎每年都有非O1/O139群霍乱弧菌散发和局部暴发的报道。主要涉及O6、O10、O11、O12、O14、O26、O34、O37、O51、O59、O97、O141和O176这13个血清群及不凝弧菌(NAGs)，而且环境与临床样本中血清群的分布并不相同。在许多地方，非O1/O139群霍乱弧菌的发病率已远远高于O1和O139群，其中，印度主要为O6、O10、O11、O34、O37、O59和O97这几个血清群[2]。NAGs在加尔各答的流行率(约2%)与中国广州报道的一致[3]。1993 1995年泰国的腹泻病例研究显示，非O1/O139群霍乱弧菌的患病率已与O1群相当[4]，主要是O6和O14血清群。另外，秘鲁主要是O10和O12血清群[5]，捷克和苏丹为O37血清群[6]，许多地方还有O141血清群的报道[7]。在南美，从1993年起，已经没有O1群霍乱弧菌引起霍乱的病例报道，而代之以O6和O34作为两个主要的血清群[8]。除了亚洲和南美洲，Ottaviani等[9]对意大利海产品及临床样本的分析显示，海产品中主要的非O1/O139群菌株属于O26(21%)和O51(16%)血清型，临床样本中为O176和O37血清型。2012年，Albuquerque等[10]报道了葡萄牙1例肝硬化患者由于非O1/O139群霍乱弧菌导致的急性腹泻而死亡，这是葡萄牙第一次关于非O1/O139群霍乱弧菌的报道。
2 致病因子
O1和O139群霍乱弧菌的主要毒力因子是霍乱毒素(CT，由ctxAB编码)和毒素共调菌毛(TCP，由tcpA编码)。与O1/O139群霍乱弧菌不同，非O1/O139群霍乱弧菌通常缺少CT和TCP。但有研究显示，在动物模型中，含有TCP的非O1/O139群霍乱菌株比不含有TCP的菌株显示出更高的感染能力[2]。另有研究提示，相对于不致病的菌株来说，含有CT和TCP的非O1/O139群霍乱弧菌具有一种选择上的优势，它们有侵袭人类肠道并变成产毒素菌株的能力[11]。
非O1/O139群霍乱弧菌是由各个不同的血清群组成的混合体，迄今为止，它们的致病机制仍不十分清楚[12]。非O1/O139群霍乱弧菌的主要致病因子有外膜蛋白(ompW)[13]、脂多糖(LPS)[2]、肠毒素(ST)[11]、蛋白酶[14]、溶血素(HlyA)[14]、磷脂酶、转录调节因子(ToxR)[1]、重复毒素(RTX)[2]等。其中外膜蛋白、脂多糖等可能对人类肠道细胞的抵御机制产生了抗性，才导致肠道中非O1、O139群霍乱弧菌的日益增多。另外，肠毒素、蛋白酶、溶血素和磷脂酶等，也能对宿主细胞造成破坏甚至最终引起细胞死亡。由hlyA编码的溶血素可以在细胞膜上形成孔隙而破坏靶细胞，在兔结肠结扎试验中，它可以引起血液和黏液的产物积聚[15]。ToxR的活性主要影响霍乱CT毒素的表达，它的存在可以激活霍乱毒素的转录[16]。RTX的存在可以加强霍乱毒素的毒性 。
Chatterjee等[2]的研究显示，非O1/O139群霍乱弧菌的脂多糖与O1、O139群霍乱菌株有很大的差别。毒力基因的分布也有显著差别：大多数菌株携带有hlyA (87%)、rtxA (81.5%)和分泌细胞毒素的因子。另外一项研究显示，94%的菌株有编码埃尔托型菌株的hlyA基因，其次是rtxA(91.4%)和rtxC(75%)[19]。 Iyer等[14]对马来西亚的霍乱菌株研究显示，他们所有的环境中非O1/O139群霍乱弧菌都可使兔及人红细胞溶解，且有90.5%的菌株含有胞外蛋白酶。Jagadeeshan等[20]对36株来自印度南部水环境中的非O1/O139群菌株的检测中，毒力基因的存在情况为toxR(100%)，rtxA(61.1%)，hlyA(50%)，mshA (33.3%)，ST(2.7%)；并且，25%的菌株都显示出了蛋白水解活性。Fernandez-Delgado等[21]对加勒比海近岸海域的非O1/O139群菌株进行分析显示，虽然它们缺失ctxA和ctxB这些基因，却能产生一些细胞外基质产物。
许多非O1/O139群霍乱弧菌携带O1/O139群霍乱弧菌没有的三型分泌系统(TTSS)，这个基因簇与副溶血霍乱弧菌有一定的同源性 。TTSS在非O1/O139群霍乱弧菌的毒力作用中有非常重要的作用[23-25]。国内有人检测了分离自浙江的非O1/O139群菌株TTSS的携带情况，85%的菌株携带有TTSS；Rahman等[26]的一项研究显示，11.9%的非O1/O139群菌株携带有TTSS基因，但所有的O1/O139群菌株TTSS均为阴性。
3 耐药性
抗生素的使用被认为是降低腹泻持续时间和量的一个很有效的方法。但发展中国家霍乱弧菌的多重抗生素耐药已成为一个普遍的问题[2]，临床上进行抗生素治疗时，抗生素敏感模式对于临床菌株的表型鉴定非常有用。四环素、甲氧苄氨嘧啶-磺胺甲基异恶唑、呋喃唑酮和萘啶酸是治疗霍乱的首选药物。然而，近来的研究却显示，大多数菌株对这些药物都产生了抗性。庆大霉素、四环素、氯霉素、新霉素、诺氟沙星等仍是霍乱弧菌的敏感药物。值得关注的是，霍乱弧菌对新霉素、四环素的抗性正在逐步增加[2]。
在印度加尔各答地区，大多数霍乱菌株对氨苄西林、呋喃唑酮、磺胺甲基异恶唑、萘啶酸已经产生了耐药。对庆大霉素(96%)、 四环素(80%)、氯霉素(80.4%)表现出较高的敏感性[2]。Chatterjee等[2]对54株非O1/O139群霍乱菌株进行分析显示，菌株对抗生素的耐药性为氨苄西林(86.5%)、呋喃唑酮(78.8%)、磺胺甲基异恶唑(50%)、萘啶酸(48.1%)。对抗生素的敏感性为新霉素(55.8%)、诺氟沙星(92.3%)、四环素(90.4%)。并且对新霉素(42.3%)和四环素(7.7%)的抗性逐步增加的菌株也在出现。另一项对印度南部水环境中非O1/O139群菌株的研究显示[16]，36株菌中抗生素耐药性情况：头孢噻肟(50%)、萘啶酸(44.4%)、链霉素和四环素(41.6%)、甲氧苄氨嘧啶(38.8%)、复方新诺明(33.3%)、呋喃唑酮(27.7%)、新霉素和氧氟沙星(19.4%)、环丙沙星、诺氟沙星、奇防线霉素(16.6%)、庆大霉素(8.3%)、氯霉素(2.7%)。且把环境菌株中耐药模式与毒力基因相比较发现，对头孢噻肟、磺胺甲基异恶唑-甲氧苄氨嘧啶和萘啶酸耐药的菌株中，hlyA、mshA和rtxA基因的携带率都比较高。提示这些药物的抗性基因可能与这些基因有关。
许多新的基因盒被逐渐发现。位于1个转移性质粒上的2个整合子——dfrA27(编码甲氧苄氨嘧啶耐药性)，aadA16(编码链霉素奇放线霉素耐药性)在1株非O1/O139群霍乱弧菌上被发现[27]。Cholix toxin (ChxA)是最近才被发现的霍乱弧菌的一种外毒素，继绿脓杆菌的外毒素A及白喉杆菌的白喉毒素后，它是真核生物2型核糖转移酶毒素延长因子的第三个部分[28]。
4 结论
非O1/O139群霍乱弧菌在某些地区的感染率甚至高于O1/O139血清群，其所携带的毒力基因也和O1/O139血清群有所不同，随着抗生素使用频率的增高，又出现了许多耐药菌株甚至多重耐药菌株，但是关于非O1/O139群霍乱弧菌的系统研究却远少于O1/O139群霍乱弧菌。因此，由非O1/O139群霍乱弧菌引起的感染，可能是公共卫生学上的一个潜在威胁，值得一提的是，在发展中国家，非O1/O139群霍乱弧菌的流行率可能被远远低估了[29]。各种各样的人口、社会、环境和生理因素，在促进非O1/O139群霍乱弧菌的传播频率及细菌的抗生素耐药增加方面可能起着重要作用。
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[2] Chatterjee S, Ghosh K, Raychoudhuri A, et al. Incidence, virulence factors, and clonality among clinical strains of non-O1, non-O139 Vibrio cholerae isolates from hospitalized diarrheal patients in Kolkata, India[J]. J Clin Microbiol, 2009, 47(4):1087-1095.
[3] Xu SH, Li YX, Li ST, et al. Epidemic condition and biological characteristics of non-O1/non-O139 Vibrio cholerae in Haizhu district of Guangzhou[J]. Chinese Journal of Preventive Medicine, 2010, 44(12):1087-1090.(in Chinese) 许少洪, 李映霞, 李少彤, 等. 广州海珠地区非O1/非0139群霍乱弧菌流行状况调查及生物学特征研究[J]. 中华预防医学杂志, 2010, 44(12):1087-1090.
[4] Dalsgaard A, Forslund A, Bodhidatta L, et al. A high proportion of Vibrio cholerae strains isolated from children with diarrhoea in Bangkok, Thailand are multiple antibiotic resistant and belong to heterogenous non-O1, non-O139 O-serotypes[J]. Epidemiol Infect, 1999, 122(2):217-226.
[5] Dalsgaard A, Albert MJ, Taylor DN, et al. Characterization of Vibrio cgolerae non-O1 serogroups obtained from an outbreak of diarrhea in Lima, Peru[J]. J ClinMicrobiol, 1995, 33(10):2715-2722.
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