2019, Vol. 14
鼠疫是由鼠疫耶尔森菌感染引起的一种人畜共患病(鼠间鼠疫和人间鼠疫), 也是我国法定传染病中的甲类传染病。鼠间鼠疫主要在啮齿类动物间流行, 鼠、旱獭等为鼠疫耶尔森菌的自然宿主, 鼠蚤是传播媒介。根据临床特征, 人间鼠疫分为腺型、肺型和败血症型, 主要症状为高热、畏寒、淋巴结肿大、皮肤黏膜出血、呼吸急促等。传播途径包括鼠蚤叮咬传播、呼吸道传播和接触传播[1]。在世界范围内鼠疫出现过3次大流行。目前我国的鼠疫防治形势依旧严峻, 主要原因是疫源地面积不断扩大、人口流动愈加频繁等。今年, 我国已确诊2例肺鼠疫和1例腺鼠疫病例。
引起鼠疫的病原体为鼠疫耶尔森菌(Yersinia pestis, Y. pestis), 又称鼠疫杆菌, 属肠杆菌科的耶尔森菌属, 为革兰阴性杆菌。鼠蚤叮咬是鼠疫最主要的传播途径, 为“鼠疫耶尔森菌-鼠蚤-宿主”的传播模式。鼠疫耶尔森菌定居在鼠蚤肠中, 不断繁殖后可造成约50%的鼠蚤发生肠道梗阻[2-3], 患肠梗阻的鼠蚤在叮咬哺乳动物时又将细菌注入正常宿主[4-5]。当哺乳动物宿主血液中鼠疫耶尔森菌的含菌量＞1×108/mL时, 鼠蚤叮咬后也可被感染, 并在几日或几周后发生肠梗阻, 然后死亡[6]。
分子系统发育分析显示, 鼠疫耶尔森菌是从假结核耶尔森菌进化而来[7]。鼠疫耶尔森菌和假结核耶尔森菌有许多共同的毒力机制, 如由70 kb左右的质粒(鼠疫耶尔森菌中的pCD1和假结核耶尔森菌中的pYV)编码的Ⅲ型分泌系统(T3SS)及铁摄取。与假结核耶尔森菌相比, 鼠疫耶尔森菌还具有其独特的传播途径和毒力机制, 是鼠蚤传播的高毒力病原体, 对人类具有高致病性。
鼠疫耶尔森菌的发病机制与其独特的毒力因子及与哺乳动物宿主的相互作用密切相关。毒力因子在昆虫和哺乳动物内有所不同。与哺乳动物的相互作用包括对宿主细胞的黏附和侵袭、细胞内繁殖及与免疫细胞的相互作用。
1 在昆虫体内的毒力因子 1.1 磷脂酶D磷脂酶D被鉴定为鼠疫耶尔森菌毒素, 由pFra质粒上的ymt基因编码[3], 可帮助鼠疫耶尔森菌在鼠蚤肠中定居和繁殖, 抵抗鼠蚤肠中活跃的各种抗菌因子有助于增强其在鼠蚤肠道中的生存率[3]。
1.2 生物膜的形成鼠疫耶尔森菌需要形成生物膜来阻断鼠蚤的前角质, 这是鼠疫通过鼠蚤传播的关键[8-9]。耶尔森菌中生物膜的形成受第二信使环双鸟苷酸(c-di-GMP)正调控[10], 且受双组分Rcs调控系统负调控。Rcs由膜蛋白RcsD和RcsC、DNA结合调节剂RcsB及辅助蛋白RcsA组成。RcsB/RcsA抑制双鸟苷酸环化酶HmsT的表达[11], 抑制生物膜产生。rcsA基因突变是假结核耶尔森菌演变成经鼠蚤传播鼠疫耶尔森菌的必需条件。在鼠疫耶尔森菌中, rcsA被灭活, 导致生物膜形成[12-13]。
2 在哺乳动物宿主体内的毒力因子 2.1 T3SST3SS作为鼠疫耶尔森菌致病的重要毒力因素, 在耶尔森菌毒力质粒pYV/pCD1中编码, 是一种在致病性革兰阴性细菌中高度保守的转运装置[14]。耶尔森菌外膜蛋白(Yersinia outer protein, Yop)构成了一系列通过T3SS直接转移到宿主细胞中的效应分子[15-17]。T3SS负责将Yop转位到宿主细胞中。一旦进入宿主细胞, Yop就会破坏信号级联, 在感染过程中发挥多效性作用：①抑制Rho GTPases, 并破坏肌动蛋白细胞骨架以抑制宿主免疫细胞的吞噬作用; ②下调促炎性细胞因子产生; ③通过多种复杂机制诱导细胞死亡[18]。目前, 已经确定的Yop效应分子有6个(YopH、YopE、YopJ/P、YpkA/YopO、YopT和YopM)[19]。
Yop效应分子的递送以及对细胞侵袭需要鼠疫耶尔森菌黏附至宿主细胞。染色体编码的Ail外膜蛋白有助于细胞附着和Yop传递[20]。Psa菌毛(pH 6抗原)是促进Yop分泌的另一个因素, 它通过抑制巨噬细胞的吞噬作用及糖鞘磷脂与磷脂酰胆碱的相互作用, 介导耶尔森菌与上皮细胞的结合[21]。
LcrV (low-calcium response V antigen, LcrV)是T3SS系统的针帽蛋白, 可诱导白细胞介素10(IL-10)产生并抑制促炎性细胞因子生成。LcrV与人免疫细胞上的甲酰基肽受体1 (formyl peptide receptor 1, FPR1)结合, 从而促进细菌效应分子的转运。缺乏FPR1的小鼠存活率显著增加, 其抗鼠疫的抗体反应也随之增高。Charlton及其团队发现, FPR1R190W是保护中性粒细胞免受鼠疫耶尔森菌T3SS破坏的候选等位基因。FPR1是人类和小鼠免疫细胞中的共同受体, 其突变或缺失可帮助小鼠和人类抵抗鼠疫耶尔森的侵袭[22]。
2.2 PlaPla是一种纤溶酶原激活剂, 由鼠疫耶尔森菌独有的质粒pPCP1编码[23]。获得pPCP1是鼠疫耶尔森菌从其祖先假结核耶尔森菌进化而来的关键[24]。Pla的主要活性是将纤溶酶原裂解为纤溶酶, 进一步降解纤维蛋白凝块、层黏连蛋白和纤连蛋白等细胞外基质蛋白, 从而促进细菌传播[25]。
Pla对一系列底物的蛋白酶活性使细菌在邻近的淋巴组织[26]和远端内脏(包括肝脏和脾脏)定殖, 促进鼠疫耶尔森菌从皮下感染部位传播[27], 被证明在原发性肺鼠疫中起作用[27]。
2.3 F1胶囊蛋白(F1a)F1a是由鼠疫耶尔森菌特有的pMT1质粒编码, 是其主要毒力因子之一。F1a在35~37 ℃下生长加速, 可以覆盖细菌表面。在感染过程中, 鼠疫耶尔森菌从巨噬细胞中被释放, 并表达大量F1a[28]。尽管F1a阴性菌株显示与野生型相似的毒力, 但F1a与其他抗吞噬因子一起有效地抑制了宿主细胞对鼠疫耶尔森菌的吞噬作用, 并在体内促进了鼠疫耶尔森菌的细胞外存活。最近研究提供了F1a抑制上皮细胞吞噬作用的直接证据[29]。
2.4 铁摄取哺乳动物宿主中存活的鼠疫耶尔森菌需具有从哺乳动物铁结合蛋白中获取铁的能力。耶尔森菌素(yersiniabactin, Ybt)铁载体所依赖的铁转运系统至关重要。铁转运系统位于不稳定的102 kb DNA片段上, 即色素沉着pigmentation (pgm)位点, 由致病性耶尔森菌共有的高致病性基因岛编码。编码铁载体Ybt依赖的铁转运系统ybt基因座包括用于Ybt铁载体合成的基因簇﹝高分子量蛋白1(HMWP1)、HMWP2 (YbtD、YbtE、YbtS、YbtT、YbtU)和Ybt摄取(YbtQ、YbtP、Psn)﹞[30]。
3 对宿主细胞的黏附和侵袭鼠疫耶尔森菌喜欢侵袭特殊类型的细胞, 如肺巨噬细胞和肺泡上皮细胞。肺炎球菌表面黏附素A (pneumococcal surfaceadhesin A, PsaA)仅在特定pH值(pH 5.0~6.0)和哺乳动物体温(37 ℃)环境中表达[31]。巨噬细胞中吞噬酶的酸化诱导耶尔森菌合成PsaA[32]。PsaA通过介导宿主细胞和细菌之间的相互作用来促进经T3SS的Yop传递[33]。采用具有psaA突变的减毒株静脉感染小鼠后, 半数致死量(LD50)升高将近100倍[34-35]。
Ail (attachment invasion locus, Ail)是一种染色体编码的小膜蛋白, 属于肠杆菌Ail/Lom外膜蛋白家族, 是鼠疫耶尔森菌的主要黏附素。鼠疫耶尔森菌KIM5株的Ail突变后(pgm-), 与细胞的结合能力降低, 通过静脉感染的小鼠减毒至原来的1‰以下。在鼻内滴入Ail缺失的强毒性CO92株细菌, 可延迟小鼠的死亡时间, 并且该突变在大鼠肺鼠疫模型中减毒约至原来的1/10万[36-37]。Ail在26 ℃和37 ℃均呈高水平表达, 可与细胞外基质的纤连蛋白、层黏连蛋白和肝素[38-40]结合, 帮助其及Yop进入宿主细胞。
Ail与包括补体抑制剂C4b结合蛋白和体外nectin(一种参与细胞附着、纤溶和抑制补体系统的宿主蛋白)在内的相关底物结合, 促进黏附和侵袭的发生[41-42]。
4 细胞内繁殖在细胞内繁殖的初始阶段, 鼠疫耶尔森菌适应哺乳动物宿主内环境十分重要。在典型的自然传播中, 被感染的鼠蚤在摄入哺乳动物血液的同时, 通过呕吐的方式将鼠疫耶尔森菌注入宿主皮下组织, 而宿主的巨噬细胞则将位于皮下组织内的耶尔森菌摄入。该过程为鼠疫耶尔森菌创造了独特的细胞内生态位, 为其后续成功进行胞内繁殖并逃避宿主免疫系统攻击提供了有效条件[43]。此后, 鼠疫耶尔森菌通过多种毒力因子(如前描述), 迅速适应哺乳动物宿主内环境, 避免被吞噬并开始启动其细胞外周期[44]。它可在体内或体外感染初始阶段的巨噬细胞内存活并完成繁殖[45], 但会被中性粒细胞和活化的巨噬细胞有效杀灭[43, 46]。专职巨噬细胞吞噬并消化细菌, 抗原呈递细胞可将细菌中的肽呈递到细胞表面, 刺激宿主防御信号, 从而清除入侵细菌。通过巨噬细胞液泡酸化, 含有截留细菌的吞噬体与溶酶体融合, 逐渐成熟为吞噬溶酶体。值得一提的是, 鼠疫耶尔森菌会抑制吞噬体的酸化及自噬, 从而使未成熟的吞噬体成为保护细菌和促进胞内繁殖的重要屏障[45]。
许多研究揭示了在宿主巨噬细胞中耶尔森菌的存活过程。Lukaszewski等研究表明, 在感染后5 d (dpi, days postinfection)才能在脾脏巨噬细胞中持续检测到鼠疫耶尔森菌, 然而在小鼠-豚鼠鼠疫模型中, 感染后72小时(hpi, hours postinfection)即可在脾中性粒细胞中检测到鼠疫耶尔森菌[43]。体外培养时, 脾中性粒细胞中的鼠疫耶尔森菌不能存活, 但脾巨噬细胞中的鼠疫耶尔森菌却可被培养, 表明中性粒细胞抑制了鼠疫耶尔森菌的生长, 而巨噬细胞则无法抑制其生长。Spinner等研究结果表明, 胞内鼠疫耶尔森菌可在人培养多形核白细胞(polymorphonuclear leukocyte, PMN)中存活并繁殖, 且大部分鼠疫耶尔森菌感染的PMN在12 hpi会发生细胞凋亡。但这些PMN可进一步被巨噬细胞识别, 被胞吞后的鼠疫耶尔森菌可继续完成存活、繁殖周期[47]。感染早期阶段, 动物的组织病理学证据表明鼠疫耶尔森菌繁殖后可在细胞外存活[43, 48]。巨噬细胞为鼠疫耶尔森菌的繁殖提供了重要的庇护场所。
Pujol等研究结果表明, 鼠疫耶尔森菌能在被γ干扰素激活的巨噬细胞中繁殖, 需要pgm位点内RipA(由ripA, ripB和ripC组成)的参与[46]。RipA为产生丁酸酯的丁酰辅酶A(CoA)转移酶, 丁酸酯可降低巨噬细胞产生一氧化氮(nitric oxide, NO)的水平[49]。低水平的NO为鼠疫耶尔森菌在巨噬细胞内的繁殖提供了条件[50]。PhoP/PhoQ系统是耶尔森菌繁殖的重要分子, 其中PhoQ是传感器, PhoP是效应器。在既往伤寒沙门菌的研究中, PhoP已被证实参与了巨噬细胞内的细菌存活和繁殖。Oyston等体外实验表明, PhoP/PhoQ对于巨噬细胞系J774A.1细胞中的耶尔森菌存活非常重要。在低pH值合并氧化应激条件下, phoP突变的LD50增加了75倍[51]。在果蝇的消化道中, 鼠疫耶尔森菌诱导PhoP/PhoQ可调节细菌对环境压力的适应力, 从而促进细菌外表面的修饰和生物膜的形成[52]。
5 与宿主免疫防御的相互作用鼠疫耶尔森菌具有多种抗炎机制, 辅助其在感染初期迅速繁殖且不被宿主杀灭。鼠疫耶尔森菌的LcrV通过与TLR2的相互作用诱导产生抗炎因子IL-10[53]; 通过T3SS系统注入Yop毒力因子而影响免疫细胞, 即YopE、YopT和YpkA破坏细胞骨架, YopH、YopE、YopT和YpkA抑制吞噬作用, YopJ下调炎症反应[54]。
鼠疫耶尔森菌能迅速抑制哺乳动物宿主的天然免疫反应, 促进其快速繁殖[55-57]。鼠疫耶尔森菌在鼠蚤叮咬附近的淋巴结中迅速繁殖, 在感染早期(6~36 hpi), 机体因无法识别进而无法产生炎症反应, 细菌从腹股沟淋巴结内逸出并迅速扩散入血, 从而定居于肝、脾、肺。在感染的后阶段, 宿主的免疫反应主要表现为炎症细胞浸润、细胞因子产生和组织坏死。用原发性肺鼠疫的小鼠鼻内滴定模型进行病理学研究, 证实了上述机制, 在感染初期的24~36 hpi无显著炎症表现, 48 hpi炎症显著活化, 3 dpi显示死亡状态[48]。另一项研究显示, 48 hpi才观察到中性粒细胞向肺部聚集, 且在此阶段无法检测到支气管肺泡灌洗液中的前纤毛化趋化因子[58]。已报道的感染鼠疫耶尔森菌的动物或培养细胞基因转录组分析均显示, 鼠疫耶尔森菌在不同感染模型中的各个阶段均可抑制天然免疫应答[56, 59-62]。由此产生的全身性炎症反应综合征可能导致弥散性血管内凝血、出血、器官衰竭和休克, 四肢和躯干出现紫癜, 坏疽可发生在手指、脚趾、耳朵和鼻子尖端[63]。
鼠疫虽然是较为古老的传染病[64], 但是在世界范围内的3次大流行对人类造成了无法磨灭的伤害。目前因疫源地面积不断扩大和人口流动的原因, 仍存在鼠疫再次大流行的风险。需要对鼠疫进行预防和控制, 以便对于暴露后的人群进行及时处理和诊治[65-66]。本文对其发病机制进行研究, 旨在为防治鼠疫提供理论知识基础, 同时也为其他病原菌的研究提供较为清晰、完善的模板。
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