单核细胞增多性李斯特菌分子进化与酸应激功能基因组学研究
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摘要
单核细胞增多性李斯特菌(简称单增李斯特菌)是重要的食源性人畜共患病原菌,可引发败血症、脑膜炎与流产等,致死率可达30%,远高于其它食源性病原菌。近年来,欧美国家李斯特菌病的发病率呈上升趋势。2007～2009年美国、加拿大和丹麦均暴发食源性李斯特菌病,共导致30人死亡。我国由于缺乏系统的李斯特菌病流行病学资料,目前无法评估其危害的严重性。
单增李斯特菌食品分离株间致病力各异。4b型(谱系Ⅰ)引起大多数的侵袭型李斯特菌病病例,且死亡率高于其他血清型；1／2a型(谱系Ⅱ)在食品中的分离率最高,主要引起人胃肠炎型李斯特菌病；谱系Ⅲ则很少引起人发病。单增李斯特菌的感染过程包括抵抗宿主内环境的应激、黏附并侵入细胞、细胞内增殖以及细胞间扩散,每一步均由特定的毒力因子介导。食源性病原菌通过消化道进入人体后,首先需要耐受胃液的酸性环境。因此,抗酸应激能力是单增李斯特菌建立感染的前提。无害李斯特菌常伴随单增李斯特菌出现在被污染的食品中,两者的生态、生化及基因组特征均非常相似,但无害李斯特菌不致病。因此,单增李斯特菌-无害李斯特菌进化枝是研究细菌致病性和毒力基因演化的良好模型。
本研究旨在探明：(1)国内食源性单增李斯特菌的分子流行病学特征与致病性；(2)单增李斯特菌谱系Ⅲ和无害李斯特菌的生物多样性及其分子进化关系；(3)单增李斯特菌精氨酸脱亚胺酶系统的抗酸应激功能及其分子机制。
1、食源性单增李斯特菌分子流行病学特征与致病性
基于iap与lmo0038的多重PCR反应,首次将鉴定李斯特菌各个种与区分单增李斯特菌谱系Ⅲ结合于一步检测体系中,适用于大批量样品的李斯特菌监测。2000～2007年中国13个省市李斯特菌平均污染率为3.8%,其中单增李斯特菌约占25.3%。其污染无季节性差异,肉类与水产品的受污染程度最为严重。采自浙江、福建的88株单增李斯特菌食品分离株中,1／2a型占58%,4b型仅占12%,M7与S19属于谱系Ⅲ。2007～2008年从5大洲29个国家进口的1275批水产品中,李斯特菌污染率为2.8%,与国内水产品相近(2.7%),其中单增李斯特菌所占的比例(91.7%)远高于国内水产品(22.2%),4b型(65.2%)取代1／2a型(13.0%)成为主导,并有流行克隆Ⅰ和Ⅱ检出。系统进化树中,流行克隆Ⅰ与我国病羊临床株亲缘关系较近,流行克隆Ⅱ位于1／2b型菌株间,而我国食源性4b分离株则位于独立的分枝。由此可见,进口水产品中致病性单增李斯特菌的危害风险性较高。上述菌株均含有第一毒力岛(LIPI-1)、inlAB(除S10)等主要毒力基因。除谱系Ⅲ菌株M7,绝大部分菌株对体外培养细胞和小鼠均具有较强致病力。ActA中1个赖氨酸重复区(PRR)的缺失并不影响细菌毒力,但可作为区分流行克隆Ⅰ和Ⅱ的遗传标志。谱系Ⅲ在系统进化树中位置特殊,可能为研究单增李斯特菌的进化提供线索。
2、单增李斯特菌谱系Ⅲ的多样性与分子进化
16S rRNA进化树中,单增李斯特菌谱系Ⅲ菌株位于单增李斯特菌、无害李斯特菌与玛氏李斯特菌之间。在基于21个基因的多位点序列分型中,13个谱系Ⅲ菌株位于3个主要分枝,分别代表亚系ⅢA、ⅢB、ⅢC。其中ⅢA又可分为3个亚枝ⅢA-1、ⅢA-2与ⅢA-3,弱毒株M7与54006属于ⅢA-3。基于46个生化指标的生化分型,将这些谱系Ⅲ菌株分为8个生化型：ⅢA-3为1型；4株ⅢA-1与ⅢA-2为2型；5株ⅢB分别为3-7型；2株ⅢC同属8型。基于37种内化素基因的内化素分型,则将谱系Ⅲ菌株分为10个内化素型,并可归为4类：第一类对应ⅢB,所含内化素基因数最少；第二类对应ⅢA-3；第三类对应ⅢC菌株；第四类对应ⅢA-1与ⅢA-2,包含的内化素基因最多。ascB-dapE内化素岛结构进一步将ⅢB与ⅢC分为ⅢB-1、ⅢB-2与ⅢC-1、ⅢC-2。
所有ⅢA-1、ⅢA-2、ⅢB与ⅢC菌株均具有与谱系Ⅰ和Ⅱ强毒株相似的胃液存活力、细胞黏附力、侵袭力以及细胞空斑形成能力,对正常小鼠与免疫抑制小鼠均具有致病力。但ⅢA-3在胃液的存活力仅为其他菌株的1／1000,在庆大霉素存在时不能形成细胞空斑,易被宿主清除,因而对正常小鼠与免疫抑制小鼠的致病力均很弱。所有谱系Ⅲ菌株均含有完整的LIPI-1、InlAB等毒力因子,其余内化素(如InlC、InlF、InlJ)及ActA中一个PRR重复区的缺失并不是导致ⅢA-3弱毒的原因。ⅢA-3菌株的LIPI-1毒力基因与inlAB的表达水平显著高于其他菌株,具有极强的体外溶脂活性。在ⅢA-3的PrfA转座突变株中,LIPI-1毒力基因与inlAB的表达量降至亲本株的1／10～1／1000。因此,ⅢA-3的毒力基因高水平表达可能由PrfA的过度表达引起。PrfA是单增李斯特菌最重要的毒力调控因子,ⅢA-3的PrfA第145位由甘氨酸(G)突变为丝氨酸(S)。该位点位于PrfA的HTH基序外侧,其突变引起PrfA空间构象改变而处于构成性激活状态,引起下游调控基因(包括膜裂解因子LLO、PC-PLC等)过度表达,细菌裂解宿主细胞的能力增强,从而使菌体暴露于机体免疫系统而被清除,进而导致弱毒。其余谱系Ⅲ菌株均为强毒株,但极少引起人发病,可能是因其在食品与环境中的分离率较低,感染人的几率较小。
ⅢA-3代表菌株M7的全基因组序列长2852640bp,编码约2970个ORF,GC含量为38.2%,高于其他谱系(37.8～38.0%)。与1／2a型、4b型强毒株相比,M7在46个区域缺失109个基因,包括ADI基因岛(lmo0036-lmo0041基因簇)、rplS-infC内化素岛、ascB-dapE内化素岛及11个疑似转录调控因子等。M7含有345个特异性基因,包括E家族毒力因子M7-28、Sigma家族蛋白M7-210、内化素M7-214与4个疑似转录调控因子等。ⅢA-3含有与强毒株相同的LIPI-1,但其23S rRNA与无害李斯特菌具有更高的同源性。基于2168个李斯特菌属保守基因的系统进化树中,ⅢA-3位于单增李斯特菌谱系Ⅰ、Ⅱ与无害李斯特菌之间。ⅢA-3既含有单增李斯特菌特异的毒力因子(如LIPI-1、InlAB、Bsh等),又与无害李斯特菌具有相似的基因缺失(如精氨酸脱亚胺酶基因岛、rplS-infC内化素岛、ascB-dapE内化素岛等)与基因插入(108个共有特异性基因),这类弱毒株可能为单增李斯特菌-无害李斯特菌进化枝的进化中间体。ⅢA-3特异性含有介导细菌水平转移的多种噬菌体相关蛋白、重组酶、整合酶、转座子蛋白与CRISPR相关蛋白,提示ⅢA-3可能具有更高的水平转移发生概率。但是,ⅢA-3无法指示该进化枝的进化方向。无害李斯特菌作为进化枝的另一极,其亚群结构可能为确定该进化枝的进化方向提供重要线索。
3、无害李斯特菌的亚群结构以及单增李斯特菌-无害李斯特菌分枝的进化关系
内化素分型与多位点序列分型将无害李斯特菌分为亚群A、B、C和D。亚群A包括内化素型1与3(除菌株0063属于亚群C),亚群B包括内化素型2与4。大多数菌株(94.2%)属于这两个亚群。亚群A、B与共同祖先的遗传距离(TMRCA)相同,提示两者出现的时间相似。但亚群A的重组率显著高于亚群B,包括重组的相对发生频率(r／m)及相对影响程度(ρ／θ)。绝大多数亚群A菌株含有完整的无害李斯特菌特异性内化素与单增李斯特菌-无害李斯特菌共有内化素。溯祖(Coalescent)模型提示亚群A近期经历了种群规模的扩张。因此,亚群A可能代表了无害李斯特菌环境适应性的进化方向。除亚群D菌株L43含有inlJ,无害李斯特菌缺失其他与黏附、侵袭、细胞内感染相关的基因,对小鼠均无致病力。无害李斯特菌的序列多态性显著低于单增李斯特菌,为相对年轻的菌种。因此,该分枝的进化方向是由单增李斯特菌至无害李斯特菌,代表细菌致病力由强变弱的罕见案例。
亚群D对应于内化素型5,在进化树上偏离其他亚群,可能是单增李斯特菌与无害李斯特菌的另一进化中间体。可通过丙氨酸-苯丙氨酸-脯氨酸芳胺酶与丙氨酸芳胺酶反应活性与无害李斯特菌其他亚群相区别。较之亚群A菌株CLIP 11262,L43在全基因组的50个区域缺失365个基因。其中部分为L43与单增李斯特菌共同缺失,部分为进化中间体L43与单增李斯特菌ⅢA-3特异缺失。L43含有单增李斯特菌特异性黏附因子InlJ,但在第11个赖氨酸重复区具有7个核苷酸的错位缺失,代表首例提前终止的InlJ。
综上所述,提出单增李斯特菌-无害李斯特菌进化枝的进化模型。单增李斯特菌1／2c型(谱系Ⅱ)代表最古老的类群,存在至少3条进化途径：一条进化为谱系Ⅰ,经1／2b至4b；一条通向ⅢB(由ⅢB-1至ⅢB-2)；另一条则进化为1／2a型(谱系Ⅱ)和ⅢA-／-2,后者进而分化为ⅢA-3与ⅢC (ⅢC-1至ⅢC-2)。单增李斯特菌ⅢA-3为进化中间体,并经由另一进化中间体无害李斯特菌亚群D,向无害李斯特菌进化(由亚群C至亚群A、B)。
4、单增李斯特菌酸应激功能基因组学研究
通过Solexa基因表达谱分析技术,在全基因组水平上比较单增李斯特菌参考菌株10403S在中性(pH 7.0)与酸性(pH 4.8)环境下基因的转录水平差异,发现有谷氨酸脱羧酶(GAD)系统与精氨酸脱亚胺酶(ADI)系统(lmo0036-lmo0043基因簇)在酸性环境中转录量明显上升。GAD系统含有3个同源基因gadD1、gadD2和gadD3。在酸性环境(pH 4.8)中,gadD2与gadD3的转录水平升高,而gadD1转录水平不变。表明GAD系统与单增李斯特菌的抗酸应激有关,该系统与inlGHE与inlGC2DE同步进化。
无论从分子进化或功能基因组学角度,ADI基因簇均引起了我们的关注。该.基因岛含有8个基因,包括arc家族成员arcABCD、aguA家族成员aguAl与aguA2、可能转录调控因子lmo0041与未知功能基因lmo0042,同时涵盖ADI系统与AgDI系统。这些基因在酸性条件(pH 4.8)的转录水平均显著高于中性条件(pH 7.0)。这些基因缺失株在中性BHI(pH7.0)的生长速率与亲本株无差异,但在酸性BHI(pH5.5)的生长速率低于亲本株；这种生长差异在酸性MEM(pH5.5)中更为明显。在人工胃液中,各缺失株的存活率亦显著低于亲本株。表明ADI系统是单增李斯特菌的抗酸应激系统。同时,各缺失株对小鼠的致病力显著低于亲本株。aguA1与aguA2编码双拷贝的鲱精胺脱亚胺酶(AgDI),但aguA2对单增李斯特菌的抗酸性发挥更重要的作用,对致病力的影响亦更为明显。
5、单增李斯特菌精氨酸脱亚胺酶/鲱精胺脱亚胺酶系统功能蛋白的作用机制
单增李斯特菌arc A(lmo0043)编码ADI,以精氨酸为反应底物。单增李斯特菌含有arg基因家族,可内源性合成精氨酸；又可在强酸性环境中摄取外源性精氨酸。精氨酸经ADI催化发生脱亚胺反应,生成瓜氨酸与氨。同时,aguAl(lmo0038)与aguA2(lmo0040)编码双拷贝的鲱精胺脱亚胺酶(AgDI),以鲱精胺为底物。单增李斯特菌可在强酸性环境中摄取外源性鲱精胺；又具有精氨酸脱羧酶活性,可介导精氨酸的脱羧反应生成内源性鲱精胺。鲱精胺经AgDI催化发生脱亚胺反应,生成氨甲酰腐胺与氨。AguA1与AguA2具有相似的亲水性与活性位点,但AguA2对单增李斯特菌的抗酸性具有更显著的影响。由此可见,ADI与AgDI分别启动了其相应的代谢通路。
ArcB兼具鸟氨酸氨甲酰转移酶(OTC)与腐胺氨甲酰转移酶(PTC)的活性,催化两组可逆的氨甲酰基转移反应,为首例可同时催化4个反应方向的氨甲酰转移酶。体外的转氨甲酰反应平衡倾向于同化方向。同化反应的最适pH呈碱性(pH8～pH10),而异化反应的最适pH为酸性(pH5～pH5.5),提示OTC/PTC在酸性环境(如胃液)中主要催化异化反应。异化方向OTC催化瓜氨酸的脱氨甲酰反应,生成鸟氨酸与氨甲酰磷酸盐;而异化方向PTC则催化氨甲酰腐胺的脱氨甲酰反应,生成腐胺与氨甲酰磷酸盐。OTC与PTC活性分别推进了ADI代谢通路与AgDI代谢通路。ArcB将这两条代谢通路联系起来,发挥承前启后的关键作用。
氨甲酰磷酸盐在氨甲酰激酶CK (lmo0039)的作用下,生成二氧化碳与氨。而鸟氨酸与腐胺通过跨膜转运因子AP (lmo0037),与胞外的精氨酸或鲱精胺进行等量交换,启动新一轮的ADI与AgDI代谢循环。该循环处于动态平衡之中。在1个ADI或AgDI循环中,1 mol精氨酸或鲱精胺生成2 mol氨。在酸性环境中,氨与细胞质中的H+结合为NH4+,提高细胞质的pH,以减轻酸应激对细胞的伤害,从而增强细菌在酸性环境(如胃液)中的存活力。
ADI基因岛如此精巧的排布背后,必然有一个缜密的调控网络系统。Lmo0041属于rpiR家族转录调控因子,ArgR为精氨酸合成抑制因子,分别在胃液中负调控与正调控ADI与AgDI代谢通路,其中Lmo0041的作用强于ArgR。ArgR同时正调控Lmo0041,更加剧了Lmo0041对ADI与AgDI通路的负调控作用。ADI基因岛中存在应激调控因子SigB与毒力调控因子PrfA的结合位点,提示ArgR与Lmo0041可能受更高一级的调控因子所调控。这些调控因子可能在不同的环境条件下,选择性激活或抑制ADI与AgDI代谢通路。由此可见,ADI与AgDI系统在级联调控网络的作用下,介导单增李斯特菌的抗酸性以及致病力。
综上所述,本论文阐明了(1)国内外食源性单增李斯特菌(除谱系Ⅲ菌株M7)均具有较强的致病力,进口水产品中单增李斯特菌的危害风险性高于我国食品体系；(2)单增李斯特菌谱系Ⅲ具有极高的生物多样性,亚系ⅢA-3菌株为弱毒,可能由毒力调控因子PrfA的第145位氨基酸发生突变引起；(3)无害李斯特菌代表相对年轻的种,包含4个亚群,其中亚群A代表环境适应性的进化方向,亚群D与单增李斯特菌ⅢA-3构成单增李斯特菌-无害李斯特菌进化枝的进化中间体,该进化枝代表细菌致病力由强变弱的罕见案例：(4)GAD系统及ADI/AgDI系统与单增李斯特菌的抗酸应激相关,ADI/AgDI系统还与细菌致病力相关；(5)ADI代谢途径与AgDI代谢途径在ADI、双拷贝AgDI、OTC/PTC与AP等功能蛋白的介导下,并行不悖地发挥抗酸应激作用；(6)ADI系统受级联调控网络的调控。
The intracellular pathogen Listeria monocytogenes is the causative agent of listeriosis, a severe invasive illness that has an extremely high mortality rate. This disease is primarily transmitted by consumption of contaminated foods. The incidence of listeriosis has increased in Europen and American countries.From 2007 through 2009, three large listeriosis outbreaks have been reported in US, Canada, and Denmark, which lead to 30 deaths and a large proportion of perinatal infections. Unfortunately, there is a paucity of systemic investigation on the prevalence of Listeria in Chinese food systems.
L. monocytogenes encompasses a diversity of strains with varying virulence and pathogenicity. While serovar 4b strains caused the vast majority of invasive listeriosis cases with a higher mortality rate than other serovars, lineage III strains are rarely associated with human listeriosis. L. monocytogenes infection process comprises several distinct stages:tolerance to adverse conditions in gastrointestinal tract (GIT), adhesion and invasion of host cells, escape from vacuole, intracellular multiplication and intercellular spread. Each stage invovles specific virulence factors. After ingestion by host, L. monocytogenes encounters the stomach with low pH. Therefore, survival in acid environments is the primary ability for L. monocytogenes to initiate infection. L. innocua is most closely related to L. monocytogenes, and they usually co-exist in food specimens.Although these two species resemble each other ecologically, biochemically and genetically, L. innocua has no pathogenic inclination. Therefore, the L. monocytogenes-L. innocua clade within the genus Listeria can be used as a model system to examine the evolution of pathogenicity.
This study was in an attempt to clarify (1)molecular epidemiology and pathogenic potential of L.monocytogenes isolates from Chinease food system and imported food products;(2) the biodiversity and evolution of L. monocytogenes-L. innocua clade;and (3)the role of arginine deiminase system in acid tolerance/resistence and its underlying molecular mechanisms.
1.Molecular epidemiology and pathogenicity of L. monocytogenes in food systems
A novel multiplex PCR, based on Imo0038 in combination with optimized iap migration profiles, was developed for simultaneous identification of Listeria species and discrimination of L. monocytogenes lineage III. The recovery rate of Listeria in Chinese food products between 2000 and 2007 was 3.7%, with L. monocytogenes accounting for 25.3%.There was no difference between the recovery rate in summer and that in winter. Of the seven main categories of food products, meat and seafood represented the major products to be contaminated by Listeria. Among the 88 selected L. monocytogenes food isolates from Zhejiang and Fujian provinces, serovar 1/2a dominated (47.7%),and the isolation of serovar 4b (6.8%) and lineageⅢ(2.4%) was low. From the 1275 batches of aquatic products imported from 29 countries, the recovery rate of Listeria was 2.8%, similar to that in Chinese aquatic products (2.7%). However, L. monocytogenes accounted for a surprisingly high proportion (91.7%) compared to that in Chinese aquatic products (22.2%).Serovar 4b predominted (65.2%), with epidemic clonesⅠ(ECⅠ) andⅡ(ECⅡ) recognized, followed by serovar 1/2a(13.0%).In the cladogram, ECI formed sister branch with clinical isolates from Chinese diseased animals, while ECⅡwas placed between 1/2b isolates.Chinese food 4b isolates occupied another branch not related to any ECs. All L. monocytogenes isolated from Chinese food systems and imported aquatic products harbored LIPI-1 and InlAB (except S10), and demonstrated virulence potential in mouse model except M7 being low-pathogenic.The absence of one proline-rich repeat (PRR) did not stop the bacterium causing listeriosis, but offered a potential marker for differentation of epidemic clonesⅠandⅡfrom phylogenic perspective. LineageⅢwas recovered at an extremely low frequency, but might serve as sources of clues for understanding the evolution history in L. monocytogenes-L. innocua clade.
2. Diversity and evolution of L. monocytogenes lineageⅢ
In the cladogram based on 16S rRNA,13 L. monocytogenes lineageⅢstrains were placed between L. monocytogenes, L. innocua and a novel species, L. marthii. The phylogenetic tree based on 21 genes revealed three major branches representing sublineagesⅢA,ⅢB andⅢC respectively.ⅢA was further separated intoⅢA-1,ⅢA-2 andⅢA-3(containing low-pathogenic strains M7 and 54006).These lineageⅢstrains were grouped into 8 biochemical types (BTs) based on 46 biochemical reactions.ⅢA-3 belonged to BT1,ⅢA-1 andⅢA-2 to BT2,ⅢB to BT3 to BT7 (5ⅢB strains representing 5 individual BT), andⅢC to BT8. These lineageⅢstrains were separated into 10 internalin type (ITs)dusted in 4 categories.ⅢB belonged to categoryⅠcontaining the least number of internalins,ⅢA-3 andⅢC to categoriesⅡandⅢrespectively, andⅢA-1 andⅢA-2 to categoryⅣwith the most number of internalins.The organization of internalin genes between ascB and dapE further classifiedⅢB into andⅢB-1 andⅢB-2, andⅢC intoⅢC-1 andⅢC-2.
AllⅢA-1,ⅢA-2,ⅢB andⅢC strains showed comparable survival ability in human gastric fluid, adhesion and invasion of epithelial cells, intracellular spread ability and pathogenicity in normal and immunocompromised mice to those of lineagesⅠandⅡstrains.Thus, the uncommon human listeriosis cases due to lineageⅢstrains might be explained by the rarity of foodborne exposure to lineageⅢ.
ⅢA-3 had an imparied survival ability in human gastric fluid and formed no visible plaques in fibroblast in the presnce of gentamycin. Also,ⅢA-3 was eliminated by host more easily than pathogenic strains, and thus exhibited negligible virulence in normal and immunocompromised mice.ⅢA-3 contained the complete version of LIPI-1 and InlAB.Lacking some internalins (e.g. InlC, InlF and InlJ) and one PRR in ActA did not contribute to the subdued virulence. PrfA is the main virulence regulator in L. monocytogenes, and the core PrfA regulon encompasses LIPI-1 and inlAB. The expression levels of LIPI-1 and InlAB inⅢA-3 were suprisingly higher than pathogenic strains, and declined drastically in the PrfA mutant inserted by transposon. Significant mutation of PrfA inⅢA-3 was found at 145 (Glycine to Serine), which introduced a repositioning of the PrfA helix-turn-helix DNA binding region in comparison to the wild-type structure. This repositioning resulted in the constitutive activation of PrfA and the overexpression of PrfA-regulated factors (e.g. LLO, PC-PLC), which faciliated the membrance-lysis process. Hence, bacteria was exposed to the immune system and easily cleared, which resulted in the reduced virulence.
The complete genome ofⅢA-3 strain M7 was sequenced by Illumina/Solexa. M7 contained one circular chromosome of 2852640bp in length with an average G+C content of 38.2%, higher than those in other lineages.There were 2970 predicted coding regions in the genome. Compared to pathogenic strains, M7 lacked 109 genes clustered in 46 loci, including ADI island, rplS-infC internalin island, ascB-dapE internalin island,11 transcriptional regulators, etc, and possessed 345 specific genes, covering those encoding virulence-associated E family protein (M7-28), Sigma family protein (M7-210),internalin (M7-214),4 transcriptional regulators, etc.ⅢA-3 harbored LIPI-1 like pathogenic strains, and had higher nucleotide identity of 23S rRNA to L. innocua than to L. monocytogenes. In the cladogram based on 2168 genes conserved in genus Listeria,ⅢA-3 were placed between L. monocytogenes lineagesⅠandⅡand L. innocua. By bearing L. monocytogenes-specific virulence genes (e.g. LIPI-1 and inlAB), and sharing similar gene deletions (e.g.ADI island, rplS-infC and ascB-dapE internalin islands) and gene insertions (e.g.108 genes existing inⅢA-3 and L. innocua) with L. innocua, L. monocytogenesⅢA-3 constituted a evolutionary intermediate between L. monocytogenes and L. innocua. In addition,ⅢA-3 possessed many specific proteins involved in horizontal gene transfer (HGT) events, e.g. phage-related proteins, site-specific recombinases, integrases, conjugative transposon proteins and CRISPR-associated proteins, suggesting a higher frequency of HGT than that in other lineages. However, IIIA-3 failed to indicate the evolutionary direction of L. monocytogenes-L. innocua clade. As the other side of the coin, L. innocua might hold the key to clarifying the evolution direction.
3.Population structure of L. innocua and evolution history of the L. monocytogenes-L. innocua clade
Based upon internalin profiling and multilocus sequence typing, L. innocua was separated into four subgroups.Subgroups A and B correlated with internalin types 1 and 3 (except strain 0063 belonging to subgroup C) and internalin types 2 and 4 respectively. The majority of L. innocua strains belonged to these two subgroups. The time to the most recent common ancestor (TMRCA) of L. innocua subgroups A and B were similar, suggesting these two subgroups appeared at approximately the same time. However, subgroup A harbored a whole set of L. monocytogenes-L. innocua common and L. innocua-specific internalin genes, and displayed strikingly higher recombination rates than those of subgroup B,including the relative frequency of occurrence of recombination versus mutation (ρ/θ) and the relative effect of recombination versus point mutation (r/m).Subgroup A also exhibited a significantly smaller exterior/interior branch length ratio than expected under the coalescent model, suggesting a recent expansion of its population size. Therefore, subgeoup A might represent the possible evolutionary direction towards adaptation to enviroments. All L. innocua strains lacked 17 virulence genes found in L. monocytogenes (except for the subgroup D strain L43 harboring inlJ) and were nonpathogenic to mice. L. innocua was genetically monophyletic compared to L. monocytogenes, representing a young species descending from L. monocytogenes. The evolutionary history in the L. monocytogenes-L. innocua clade represents a rare example of evolution towards reduced virulence of pathogens.
Subgroup D, which correlated with internalin type 5,branched off from the other three subgroups, and served as another evolutionary linkage between L. monocytogenes and L. innocua. This subgroup could be differentiated from other subgroups by Asp-Phe-Pro arylamidase and alanine arylamidase reactions.Compared to subgroup A strain CLIP11262, subgroup D lacked 365 genes clustered in 50 loci, some of which were also absent in L. monocytogenes or L. monocytogenes IIIA-3. Subgroup D contained L. monocytogenes-specific virulece gene inlJ. However, this gene carried a premature stop codon mutation that led to production of a truncated and possibly nonfunctional InlJ due to a non-in-frame deletion of seven nucleotide acids within the 11th PRR. Thus, subgroup D failed to invade and spread efficiently.
Overall, a stepwise evolution model of L. monocytogenes-L. innocua clade was demonstrated. If we consider gene deletion as an important force in Listeria evolution, L. monocytogenes serovar 1/2c (lineageⅡ) is more ancestral in this clade, and evolved in three directions. One evolved into serovar 4b (lineageⅠ) via serovar 1/2b (lineageⅠ); one gave rise toⅢB (fromⅢB-1 toⅢB-2);and the other turned into serovar 1/2a (lineageⅡ) andⅢA-1/2, and the latter further intoⅢC (fromⅢC-1 toⅢC-2) andⅡA-3.ⅢA-3 evolved into L. innocua via subgroup D.
4. Functional genomics of L. monocytogenes under acidic conditions
Based upon the comparison of gene transcription profiling at neutral (pH7.0) and acidic (pH4.8) conditions using Solexa genome analysis system, two systems were identified from the whole genome of 10403S with elevated transcriptional levels under acidic conditions.One was the glutamate decarboxylase (GAD) system, and the other was the putative arginine deiminase (ADI) system (lmo0036-lmo0043 cluster). The GAD system involved three GAD paralogs (gadDl,gadD2, gadD3) located in three distinct loci.The transcription of gadD2 and gadD3 were increased under acidic condition, indicating a role of GAD system in acid tolerance. Moreover, it is suggested that GAD system co-evolved with inlGHE and inlGC2DE.
From perspectives on molecular evolution and functional genomics, ADI gene island is of great interest to us.This island comprised eight genes, arc family genes arcABCD, aguA family genes aguAl and aguA2, one putative transcriptional regulator lmo0041,and one unknown gene lmo0042, which involved in arginine deiminase and agmatine deiminase systems.The transcription of those genes were increased under acidic condition relative to those under neutral condition. The AarcA,ΔarcB,ΔarcD,ΔaguA1 andΔaguA2 null mutants exhibited impaired growth rate under low pH (pH 5.5).Deletion of these genes also led to a decreased survival rates in synthetic human gastric fluid (pH 2.5).In addition, these knock-out mutants demonstrated a lower pathogenicity to mice relative to wild-type strain. Remarkably, aguAl and aguA2 represented two agmatine deiminase (AgDI) paralogs, but AguA2 contributed to acid tolerance and pathogenicity more effectively.
5. Molecular mechanisms of the arginine deiminase-agmatine deiminase system in L. monocytogenes
arcA (lmo0043) encoded ADI using arginine as substrate. L. monocytogenes harbored the whole arg gene family, suggesting arginine could be synthesized de novo. Also, L.monocytogenes was able to uptake extracellular arginine under strong acid conditions.ADI triggered the ADI pathway, and mediated the first reaction producing citrullin and ammonia. aguAl (lmo0038) and aguA2 (lmo0040) encoded two AgDI paralogs with agmatine as substrate.L. monocytogenes was able to produce agmatine from arginine using arginine decarboxylase, and uptake extracellular agmatine under strong acid conditions. AgDI initiated the AgDI pathway, and mediated the first reaction producing carbamoylputrescine and ammonia. Interestingly, although AguAl and AguA2 showed similar hydrophilicity and contained similar active sites, AguA2 played a more important role in acid tolerance.
ArcB (lmo0036) displayed the ornithine carbamoyltransferase (OTC) and putrescine carbamoyltransferase (PTC) activities, representing the first example of carbamoyltransferase responsible for two sets of reversible reactions,in vitro kinetic studies showed that the equilibrium of the reaction lied overwhelmingly towards the formation of citrulline or carbamoylputrescine (anabolic reaction).While the optimum pH for anabolic reactions were at pH 8 to pH 10, the optimum pH for catabolic reactions were at pH 5 to pH 5.5,indicating ArcB possibly served as catabolic OTC or PTC under acidic conditions. While catabolic OTC mediated the reaction yielding ornitine and carbamoyl phosphate, catabolic PTC mediated reaction with the products of putrescine and carbamoyl phosphate. Thus, ArcB linked the second and following reaction steps, and promoted the ADI and AgDI pathways.
Carbamoyl phosphate turned into ammonia, carbon dioxide and ATP by carbamate kinase (CK).Ornithine or putrescine was transported out of the cell in exchange for a molecule of arginine or agmatine by a membrane-bound antiport (AP) encoded by arcD (lmo0037), initiating a new metabolic circle at a state of dynamic equilibrium. For each mole of arginine catabolized via the ADI or AgDI pathway, two moles of ammonia were produced. This ammonia combined with intracellular cytoplasmic protons to yield ammonium inos (NH4+), thereby alleviating acidification of the cytoplasm and maintaining pH homeostasis.
Beneath the exquisite organization of ADI system, it revealed a rigorous transcriptional network. Lmo0041,a rpiR family transcriptional regulator, and ArgR, an arginine biosynthetic repressor, regulated ADI/AgDI pathways negatively and positively in the synthetic human gastric fluid. The repressive function of Lmo0041 took precedence over the activation of the ADI system mediated by ArgR. ArgR also elevated the expression of Lmo0041,which further facilitated its repression of ADI system. PrfA and stress regulator SigB might be at the top of the hierarchy of regulatory network, regulating ADI system as well as ArgR and Lmo0041,evidenced by the potential PrfA and SigB binding sites proceeding the genes in ADI gene island as well as argR.These regulators activated or repressed the ADI system under varied conditions, which mediated listerial acid tolerance and pathogenicity.
In conclusion, this study demonstrated that(1)L. monocytogenes food isolates (except lineageⅢisolate M7) all exhibit virulence potential, among which the isolates from imported aquatic products pose higher risk than those from Chinese food system; (2) L. monocytogenes lineageⅢencompasses a diversity of sublineages, with sublineage IIIA-3 showing low virulence which possibly caused by G145S mutation in PrfA; (3)L. innocua is a young species, and comprises four subgroups, with subgroup A representing the possible evolutionary direction towards adaptation to enviroments, and subgroup D together with L. monocytogenes sublineageⅢA-3 serve as evolutionary intermediates of the L. monocytogenes-L. innocua clade, representing a rare example of evolution towards reduced virulence of pathogens;(4) GAD and ADI systems contribute to the acid stress responses in L. monocytogenes, and ADI system is also involved in the listerial pathogenesis; (5) ADI pathway and AgDI pathway are mediated by functional proteins, including ADI, two paralogs of AgDI, OTC/PTC and AP;and (6) ADI system is under the regulatory network.
单增李斯特菌食品分离株间致病力各异。4b型(谱系Ⅰ)引起大多数的侵袭型李斯特菌病病例,且死亡率高于其他血清型；1／2a型(谱系Ⅱ)在食品中的分离率最高,主要引起人胃肠炎型李斯特菌病；谱系Ⅲ则很少引起人发病。单增李斯特菌的感染过程包括抵抗宿主内环境的应激、黏附并侵入细胞、细胞内增殖以及细胞间扩散,每一步均由特定的毒力因子介导。食源性病原菌通过消化道进入人体后,首先需要耐受胃液的酸性环境。因此,抗酸应激能力是单增李斯特菌建立感染的前提。无害李斯特菌常伴随单增李斯特菌出现在被污染的食品中,两者的生态、生化及基因组特征均非常相似,但无害李斯特菌不致病。因此,单增李斯特菌-无害李斯特菌进化枝是研究细菌致病性和毒力基因演化的良好模型。
本研究旨在探明：(1)国内食源性单增李斯特菌的分子流行病学特征与致病性；(2)单增李斯特菌谱系Ⅲ和无害李斯特菌的生物多样性及其分子进化关系；(3)单增李斯特菌精氨酸脱亚胺酶系统的抗酸应激功能及其分子机制。
1、食源性单增李斯特菌分子流行病学特征与致病性
基于iap与lmo0038的多重PCR反应,首次将鉴定李斯特菌各个种与区分单增李斯特菌谱系Ⅲ结合于一步检测体系中,适用于大批量样品的李斯特菌监测。2000～2007年中国13个省市李斯特菌平均污染率为3.8%,其中单增李斯特菌约占25.3%。其污染无季节性差异,肉类与水产品的受污染程度最为严重。采自浙江、福建的88株单增李斯特菌食品分离株中,1／2a型占58%,4b型仅占12%,M7与S19属于谱系Ⅲ。2007～2008年从5大洲29个国家进口的1275批水产品中,李斯特菌污染率为2.8%,与国内水产品相近(2.7%),其中单增李斯特菌所占的比例(91.7%)远高于国内水产品(22.2%),4b型(65.2%)取代1／2a型(13.0%)成为主导,并有流行克隆Ⅰ和Ⅱ检出。系统进化树中,流行克隆Ⅰ与我国病羊临床株亲缘关系较近,流行克隆Ⅱ位于1／2b型菌株间,而我国食源性4b分离株则位于独立的分枝。由此可见,进口水产品中致病性单增李斯特菌的危害风险性较高。上述菌株均含有第一毒力岛(LIPI-1)、inlAB(除S10)等主要毒力基因。除谱系Ⅲ菌株M7,绝大部分菌株对体外培养细胞和小鼠均具有较强致病力。ActA中1个赖氨酸重复区(PRR)的缺失并不影响细菌毒力,但可作为区分流行克隆Ⅰ和Ⅱ的遗传标志。谱系Ⅲ在系统进化树中位置特殊,可能为研究单增李斯特菌的进化提供线索。
2、单增李斯特菌谱系Ⅲ的多样性与分子进化
16S rRNA进化树中,单增李斯特菌谱系Ⅲ菌株位于单增李斯特菌、无害李斯特菌与玛氏李斯特菌之间。在基于21个基因的多位点序列分型中,13个谱系Ⅲ菌株位于3个主要分枝,分别代表亚系ⅢA、ⅢB、ⅢC。其中ⅢA又可分为3个亚枝ⅢA-1、ⅢA-2与ⅢA-3,弱毒株M7与54006属于ⅢA-3。基于46个生化指标的生化分型,将这些谱系Ⅲ菌株分为8个生化型：ⅢA-3为1型；4株ⅢA-1与ⅢA-2为2型；5株ⅢB分别为3-7型；2株ⅢC同属8型。基于37种内化素基因的内化素分型,则将谱系Ⅲ菌株分为10个内化素型,并可归为4类：第一类对应ⅢB,所含内化素基因数最少；第二类对应ⅢA-3；第三类对应ⅢC菌株；第四类对应ⅢA-1与ⅢA-2,包含的内化素基因最多。ascB-dapE内化素岛结构进一步将ⅢB与ⅢC分为ⅢB-1、ⅢB-2与ⅢC-1、ⅢC-2。
所有ⅢA-1、ⅢA-2、ⅢB与ⅢC菌株均具有与谱系Ⅰ和Ⅱ强毒株相似的胃液存活力、细胞黏附力、侵袭力以及细胞空斑形成能力,对正常小鼠与免疫抑制小鼠均具有致病力。但ⅢA-3在胃液的存活力仅为其他菌株的1／1000,在庆大霉素存在时不能形成细胞空斑,易被宿主清除,因而对正常小鼠与免疫抑制小鼠的致病力均很弱。所有谱系Ⅲ菌株均含有完整的LIPI-1、InlAB等毒力因子,其余内化素(如InlC、InlF、InlJ)及ActA中一个PRR重复区的缺失并不是导致ⅢA-3弱毒的原因。ⅢA-3菌株的LIPI-1毒力基因与inlAB的表达水平显著高于其他菌株,具有极强的体外溶脂活性。在ⅢA-3的PrfA转座突变株中,LIPI-1毒力基因与inlAB的表达量降至亲本株的1／10～1／1000。因此,ⅢA-3的毒力基因高水平表达可能由PrfA的过度表达引起。PrfA是单增李斯特菌最重要的毒力调控因子,ⅢA-3的PrfA第145位由甘氨酸(G)突变为丝氨酸(S)。该位点位于PrfA的HTH基序外侧,其突变引起PrfA空间构象改变而处于构成性激活状态,引起下游调控基因(包括膜裂解因子LLO、PC-PLC等)过度表达,细菌裂解宿主细胞的能力增强,从而使菌体暴露于机体免疫系统而被清除,进而导致弱毒。其余谱系Ⅲ菌株均为强毒株,但极少引起人发病,可能是因其在食品与环境中的分离率较低,感染人的几率较小。
ⅢA-3代表菌株M7的全基因组序列长2852640bp,编码约2970个ORF,GC含量为38.2%,高于其他谱系(37.8～38.0%)。与1／2a型、4b型强毒株相比,M7在46个区域缺失109个基因,包括ADI基因岛(lmo0036-lmo0041基因簇)、rplS-infC内化素岛、ascB-dapE内化素岛及11个疑似转录调控因子等。M7含有345个特异性基因,包括E家族毒力因子M7-28、Sigma家族蛋白M7-210、内化素M7-214与4个疑似转录调控因子等。ⅢA-3含有与强毒株相同的LIPI-1,但其23S rRNA与无害李斯特菌具有更高的同源性。基于2168个李斯特菌属保守基因的系统进化树中,ⅢA-3位于单增李斯特菌谱系Ⅰ、Ⅱ与无害李斯特菌之间。ⅢA-3既含有单增李斯特菌特异的毒力因子(如LIPI-1、InlAB、Bsh等),又与无害李斯特菌具有相似的基因缺失(如精氨酸脱亚胺酶基因岛、rplS-infC内化素岛、ascB-dapE内化素岛等)与基因插入(108个共有特异性基因),这类弱毒株可能为单增李斯特菌-无害李斯特菌进化枝的进化中间体。ⅢA-3特异性含有介导细菌水平转移的多种噬菌体相关蛋白、重组酶、整合酶、转座子蛋白与CRISPR相关蛋白,提示ⅢA-3可能具有更高的水平转移发生概率。但是,ⅢA-3无法指示该进化枝的进化方向。无害李斯特菌作为进化枝的另一极,其亚群结构可能为确定该进化枝的进化方向提供重要线索。
3、无害李斯特菌的亚群结构以及单增李斯特菌-无害李斯特菌分枝的进化关系
内化素分型与多位点序列分型将无害李斯特菌分为亚群A、B、C和D。亚群A包括内化素型1与3(除菌株0063属于亚群C),亚群B包括内化素型2与4。大多数菌株(94.2%)属于这两个亚群。亚群A、B与共同祖先的遗传距离(TMRCA)相同,提示两者出现的时间相似。但亚群A的重组率显著高于亚群B,包括重组的相对发生频率(r／m)及相对影响程度(ρ／θ)。绝大多数亚群A菌株含有完整的无害李斯特菌特异性内化素与单增李斯特菌-无害李斯特菌共有内化素。溯祖(Coalescent)模型提示亚群A近期经历了种群规模的扩张。因此,亚群A可能代表了无害李斯特菌环境适应性的进化方向。除亚群D菌株L43含有inlJ,无害李斯特菌缺失其他与黏附、侵袭、细胞内感染相关的基因,对小鼠均无致病力。无害李斯特菌的序列多态性显著低于单增李斯特菌,为相对年轻的菌种。因此,该分枝的进化方向是由单增李斯特菌至无害李斯特菌,代表细菌致病力由强变弱的罕见案例。
亚群D对应于内化素型5,在进化树上偏离其他亚群,可能是单增李斯特菌与无害李斯特菌的另一进化中间体。可通过丙氨酸-苯丙氨酸-脯氨酸芳胺酶与丙氨酸芳胺酶反应活性与无害李斯特菌其他亚群相区别。较之亚群A菌株CLIP 11262,L43在全基因组的50个区域缺失365个基因。其中部分为L43与单增李斯特菌共同缺失,部分为进化中间体L43与单增李斯特菌ⅢA-3特异缺失。L43含有单增李斯特菌特异性黏附因子InlJ,但在第11个赖氨酸重复区具有7个核苷酸的错位缺失,代表首例提前终止的InlJ。
综上所述,提出单增李斯特菌-无害李斯特菌进化枝的进化模型。单增李斯特菌1／2c型(谱系Ⅱ)代表最古老的类群,存在至少3条进化途径：一条进化为谱系Ⅰ,经1／2b至4b；一条通向ⅢB(由ⅢB-1至ⅢB-2)；另一条则进化为1／2a型(谱系Ⅱ)和ⅢA-／-2,后者进而分化为ⅢA-3与ⅢC (ⅢC-1至ⅢC-2)。单增李斯特菌ⅢA-3为进化中间体,并经由另一进化中间体无害李斯特菌亚群D,向无害李斯特菌进化(由亚群C至亚群A、B)。
4、单增李斯特菌酸应激功能基因组学研究
通过Solexa基因表达谱分析技术,在全基因组水平上比较单增李斯特菌参考菌株10403S在中性(pH 7.0)与酸性(pH 4.8)环境下基因的转录水平差异,发现有谷氨酸脱羧酶(GAD)系统与精氨酸脱亚胺酶(ADI)系统(lmo0036-lmo0043基因簇)在酸性环境中转录量明显上升。GAD系统含有3个同源基因gadD1、gadD2和gadD3。在酸性环境(pH 4.8)中,gadD2与gadD3的转录水平升高,而gadD1转录水平不变。表明GAD系统与单增李斯特菌的抗酸应激有关,该系统与inlGHE与inlGC2DE同步进化。
无论从分子进化或功能基因组学角度,ADI基因簇均引起了我们的关注。该.基因岛含有8个基因,包括arc家族成员arcABCD、aguA家族成员aguAl与aguA2、可能转录调控因子lmo0041与未知功能基因lmo0042,同时涵盖ADI系统与AgDI系统。这些基因在酸性条件(pH 4.8)的转录水平均显著高于中性条件(pH 7.0)。这些基因缺失株在中性BHI(pH7.0)的生长速率与亲本株无差异,但在酸性BHI(pH5.5)的生长速率低于亲本株；这种生长差异在酸性MEM(pH5.5)中更为明显。在人工胃液中,各缺失株的存活率亦显著低于亲本株。表明ADI系统是单增李斯特菌的抗酸应激系统。同时,各缺失株对小鼠的致病力显著低于亲本株。aguA1与aguA2编码双拷贝的鲱精胺脱亚胺酶(AgDI),但aguA2对单增李斯特菌的抗酸性发挥更重要的作用,对致病力的影响亦更为明显。
5、单增李斯特菌精氨酸脱亚胺酶/鲱精胺脱亚胺酶系统功能蛋白的作用机制
单增李斯特菌arc A(lmo0043)编码ADI,以精氨酸为反应底物。单增李斯特菌含有arg基因家族,可内源性合成精氨酸；又可在强酸性环境中摄取外源性精氨酸。精氨酸经ADI催化发生脱亚胺反应,生成瓜氨酸与氨。同时,aguAl(lmo0038)与aguA2(lmo0040)编码双拷贝的鲱精胺脱亚胺酶(AgDI),以鲱精胺为底物。单增李斯特菌可在强酸性环境中摄取外源性鲱精胺；又具有精氨酸脱羧酶活性,可介导精氨酸的脱羧反应生成内源性鲱精胺。鲱精胺经AgDI催化发生脱亚胺反应,生成氨甲酰腐胺与氨。AguA1与AguA2具有相似的亲水性与活性位点,但AguA2对单增李斯特菌的抗酸性具有更显著的影响。由此可见,ADI与AgDI分别启动了其相应的代谢通路。
ArcB兼具鸟氨酸氨甲酰转移酶(OTC)与腐胺氨甲酰转移酶(PTC)的活性,催化两组可逆的氨甲酰基转移反应,为首例可同时催化4个反应方向的氨甲酰转移酶。体外的转氨甲酰反应平衡倾向于同化方向。同化反应的最适pH呈碱性(pH8～pH10),而异化反应的最适pH为酸性(pH5～pH5.5),提示OTC/PTC在酸性环境(如胃液)中主要催化异化反应。异化方向OTC催化瓜氨酸的脱氨甲酰反应,生成鸟氨酸与氨甲酰磷酸盐;而异化方向PTC则催化氨甲酰腐胺的脱氨甲酰反应,生成腐胺与氨甲酰磷酸盐。OTC与PTC活性分别推进了ADI代谢通路与AgDI代谢通路。ArcB将这两条代谢通路联系起来,发挥承前启后的关键作用。
氨甲酰磷酸盐在氨甲酰激酶CK (lmo0039)的作用下,生成二氧化碳与氨。而鸟氨酸与腐胺通过跨膜转运因子AP (lmo0037),与胞外的精氨酸或鲱精胺进行等量交换,启动新一轮的ADI与AgDI代谢循环。该循环处于动态平衡之中。在1个ADI或AgDI循环中,1 mol精氨酸或鲱精胺生成2 mol氨。在酸性环境中,氨与细胞质中的H+结合为NH4+,提高细胞质的pH,以减轻酸应激对细胞的伤害,从而增强细菌在酸性环境(如胃液)中的存活力。
ADI基因岛如此精巧的排布背后,必然有一个缜密的调控网络系统。Lmo0041属于rpiR家族转录调控因子,ArgR为精氨酸合成抑制因子,分别在胃液中负调控与正调控ADI与AgDI代谢通路,其中Lmo0041的作用强于ArgR。ArgR同时正调控Lmo0041,更加剧了Lmo0041对ADI与AgDI通路的负调控作用。ADI基因岛中存在应激调控因子SigB与毒力调控因子PrfA的结合位点,提示ArgR与Lmo0041可能受更高一级的调控因子所调控。这些调控因子可能在不同的环境条件下,选择性激活或抑制ADI与AgDI代谢通路。由此可见,ADI与AgDI系统在级联调控网络的作用下,介导单增李斯特菌的抗酸性以及致病力。
综上所述,本论文阐明了(1)国内外食源性单增李斯特菌(除谱系Ⅲ菌株M7)均具有较强的致病力,进口水产品中单增李斯特菌的危害风险性高于我国食品体系；(2)单增李斯特菌谱系Ⅲ具有极高的生物多样性,亚系ⅢA-3菌株为弱毒,可能由毒力调控因子PrfA的第145位氨基酸发生突变引起；(3)无害李斯特菌代表相对年轻的种,包含4个亚群,其中亚群A代表环境适应性的进化方向,亚群D与单增李斯特菌ⅢA-3构成单增李斯特菌-无害李斯特菌进化枝的进化中间体,该进化枝代表细菌致病力由强变弱的罕见案例：(4)GAD系统及ADI/AgDI系统与单增李斯特菌的抗酸应激相关,ADI/AgDI系统还与细菌致病力相关；(5)ADI代谢途径与AgDI代谢途径在ADI、双拷贝AgDI、OTC/PTC与AP等功能蛋白的介导下,并行不悖地发挥抗酸应激作用；(6)ADI系统受级联调控网络的调控。
The intracellular pathogen Listeria monocytogenes is the causative agent of listeriosis, a severe invasive illness that has an extremely high mortality rate. This disease is primarily transmitted by consumption of contaminated foods. The incidence of listeriosis has increased in Europen and American countries.From 2007 through 2009, three large listeriosis outbreaks have been reported in US, Canada, and Denmark, which lead to 30 deaths and a large proportion of perinatal infections. Unfortunately, there is a paucity of systemic investigation on the prevalence of Listeria in Chinese food systems.
L. monocytogenes encompasses a diversity of strains with varying virulence and pathogenicity. While serovar 4b strains caused the vast majority of invasive listeriosis cases with a higher mortality rate than other serovars, lineage III strains are rarely associated with human listeriosis. L. monocytogenes infection process comprises several distinct stages:tolerance to adverse conditions in gastrointestinal tract (GIT), adhesion and invasion of host cells, escape from vacuole, intracellular multiplication and intercellular spread. Each stage invovles specific virulence factors. After ingestion by host, L. monocytogenes encounters the stomach with low pH. Therefore, survival in acid environments is the primary ability for L. monocytogenes to initiate infection. L. innocua is most closely related to L. monocytogenes, and they usually co-exist in food specimens.Although these two species resemble each other ecologically, biochemically and genetically, L. innocua has no pathogenic inclination. Therefore, the L. monocytogenes-L. innocua clade within the genus Listeria can be used as a model system to examine the evolution of pathogenicity.
This study was in an attempt to clarify (1)molecular epidemiology and pathogenic potential of L.monocytogenes isolates from Chinease food system and imported food products;(2) the biodiversity and evolution of L. monocytogenes-L. innocua clade;and (3)the role of arginine deiminase system in acid tolerance/resistence and its underlying molecular mechanisms.
1.Molecular epidemiology and pathogenicity of L. monocytogenes in food systems
A novel multiplex PCR, based on Imo0038 in combination with optimized iap migration profiles, was developed for simultaneous identification of Listeria species and discrimination of L. monocytogenes lineage III. The recovery rate of Listeria in Chinese food products between 2000 and 2007 was 3.7%, with L. monocytogenes accounting for 25.3%.There was no difference between the recovery rate in summer and that in winter. Of the seven main categories of food products, meat and seafood represented the major products to be contaminated by Listeria. Among the 88 selected L. monocytogenes food isolates from Zhejiang and Fujian provinces, serovar 1/2a dominated (47.7%),and the isolation of serovar 4b (6.8%) and lineageⅢ(2.4%) was low. From the 1275 batches of aquatic products imported from 29 countries, the recovery rate of Listeria was 2.8%, similar to that in Chinese aquatic products (2.7%). However, L. monocytogenes accounted for a surprisingly high proportion (91.7%) compared to that in Chinese aquatic products (22.2%).Serovar 4b predominted (65.2%), with epidemic clonesⅠ(ECⅠ) andⅡ(ECⅡ) recognized, followed by serovar 1/2a(13.0%).In the cladogram, ECI formed sister branch with clinical isolates from Chinese diseased animals, while ECⅡwas placed between 1/2b isolates.Chinese food 4b isolates occupied another branch not related to any ECs. All L. monocytogenes isolated from Chinese food systems and imported aquatic products harbored LIPI-1 and InlAB (except S10), and demonstrated virulence potential in mouse model except M7 being low-pathogenic.The absence of one proline-rich repeat (PRR) did not stop the bacterium causing listeriosis, but offered a potential marker for differentation of epidemic clonesⅠandⅡfrom phylogenic perspective. LineageⅢwas recovered at an extremely low frequency, but might serve as sources of clues for understanding the evolution history in L. monocytogenes-L. innocua clade.
2. Diversity and evolution of L. monocytogenes lineageⅢ
In the cladogram based on 16S rRNA,13 L. monocytogenes lineageⅢstrains were placed between L. monocytogenes, L. innocua and a novel species, L. marthii. The phylogenetic tree based on 21 genes revealed three major branches representing sublineagesⅢA,ⅢB andⅢC respectively.ⅢA was further separated intoⅢA-1,ⅢA-2 andⅢA-3(containing low-pathogenic strains M7 and 54006).These lineageⅢstrains were grouped into 8 biochemical types (BTs) based on 46 biochemical reactions.ⅢA-3 belonged to BT1,ⅢA-1 andⅢA-2 to BT2,ⅢB to BT3 to BT7 (5ⅢB strains representing 5 individual BT), andⅢC to BT8. These lineageⅢstrains were separated into 10 internalin type (ITs)dusted in 4 categories.ⅢB belonged to categoryⅠcontaining the least number of internalins,ⅢA-3 andⅢC to categoriesⅡandⅢrespectively, andⅢA-1 andⅢA-2 to categoryⅣwith the most number of internalins.The organization of internalin genes between ascB and dapE further classifiedⅢB into andⅢB-1 andⅢB-2, andⅢC intoⅢC-1 andⅢC-2.
AllⅢA-1,ⅢA-2,ⅢB andⅢC strains showed comparable survival ability in human gastric fluid, adhesion and invasion of epithelial cells, intracellular spread ability and pathogenicity in normal and immunocompromised mice to those of lineagesⅠandⅡstrains.Thus, the uncommon human listeriosis cases due to lineageⅢstrains might be explained by the rarity of foodborne exposure to lineageⅢ.
ⅢA-3 had an imparied survival ability in human gastric fluid and formed no visible plaques in fibroblast in the presnce of gentamycin. Also,ⅢA-3 was eliminated by host more easily than pathogenic strains, and thus exhibited negligible virulence in normal and immunocompromised mice.ⅢA-3 contained the complete version of LIPI-1 and InlAB.Lacking some internalins (e.g. InlC, InlF and InlJ) and one PRR in ActA did not contribute to the subdued virulence. PrfA is the main virulence regulator in L. monocytogenes, and the core PrfA regulon encompasses LIPI-1 and inlAB. The expression levels of LIPI-1 and InlAB inⅢA-3 were suprisingly higher than pathogenic strains, and declined drastically in the PrfA mutant inserted by transposon. Significant mutation of PrfA inⅢA-3 was found at 145 (Glycine to Serine), which introduced a repositioning of the PrfA helix-turn-helix DNA binding region in comparison to the wild-type structure. This repositioning resulted in the constitutive activation of PrfA and the overexpression of PrfA-regulated factors (e.g. LLO, PC-PLC), which faciliated the membrance-lysis process. Hence, bacteria was exposed to the immune system and easily cleared, which resulted in the reduced virulence.
The complete genome ofⅢA-3 strain M7 was sequenced by Illumina/Solexa. M7 contained one circular chromosome of 2852640bp in length with an average G+C content of 38.2%, higher than those in other lineages.There were 2970 predicted coding regions in the genome. Compared to pathogenic strains, M7 lacked 109 genes clustered in 46 loci, including ADI island, rplS-infC internalin island, ascB-dapE internalin island,11 transcriptional regulators, etc, and possessed 345 specific genes, covering those encoding virulence-associated E family protein (M7-28), Sigma family protein (M7-210),internalin (M7-214),4 transcriptional regulators, etc.ⅢA-3 harbored LIPI-1 like pathogenic strains, and had higher nucleotide identity of 23S rRNA to L. innocua than to L. monocytogenes. In the cladogram based on 2168 genes conserved in genus Listeria,ⅢA-3 were placed between L. monocytogenes lineagesⅠandⅡand L. innocua. By bearing L. monocytogenes-specific virulence genes (e.g. LIPI-1 and inlAB), and sharing similar gene deletions (e.g.ADI island, rplS-infC and ascB-dapE internalin islands) and gene insertions (e.g.108 genes existing inⅢA-3 and L. innocua) with L. innocua, L. monocytogenesⅢA-3 constituted a evolutionary intermediate between L. monocytogenes and L. innocua. In addition,ⅢA-3 possessed many specific proteins involved in horizontal gene transfer (HGT) events, e.g. phage-related proteins, site-specific recombinases, integrases, conjugative transposon proteins and CRISPR-associated proteins, suggesting a higher frequency of HGT than that in other lineages. However, IIIA-3 failed to indicate the evolutionary direction of L. monocytogenes-L. innocua clade. As the other side of the coin, L. innocua might hold the key to clarifying the evolution direction.
3.Population structure of L. innocua and evolution history of the L. monocytogenes-L. innocua clade
Based upon internalin profiling and multilocus sequence typing, L. innocua was separated into four subgroups.Subgroups A and B correlated with internalin types 1 and 3 (except strain 0063 belonging to subgroup C) and internalin types 2 and 4 respectively. The majority of L. innocua strains belonged to these two subgroups. The time to the most recent common ancestor (TMRCA) of L. innocua subgroups A and B were similar, suggesting these two subgroups appeared at approximately the same time. However, subgroup A harbored a whole set of L. monocytogenes-L. innocua common and L. innocua-specific internalin genes, and displayed strikingly higher recombination rates than those of subgroup B,including the relative frequency of occurrence of recombination versus mutation (ρ/θ) and the relative effect of recombination versus point mutation (r/m).Subgroup A also exhibited a significantly smaller exterior/interior branch length ratio than expected under the coalescent model, suggesting a recent expansion of its population size. Therefore, subgeoup A might represent the possible evolutionary direction towards adaptation to enviroments. All L. innocua strains lacked 17 virulence genes found in L. monocytogenes (except for the subgroup D strain L43 harboring inlJ) and were nonpathogenic to mice. L. innocua was genetically monophyletic compared to L. monocytogenes, representing a young species descending from L. monocytogenes. The evolutionary history in the L. monocytogenes-L. innocua clade represents a rare example of evolution towards reduced virulence of pathogens.
Subgroup D, which correlated with internalin type 5,branched off from the other three subgroups, and served as another evolutionary linkage between L. monocytogenes and L. innocua. This subgroup could be differentiated from other subgroups by Asp-Phe-Pro arylamidase and alanine arylamidase reactions.Compared to subgroup A strain CLIP11262, subgroup D lacked 365 genes clustered in 50 loci, some of which were also absent in L. monocytogenes or L. monocytogenes IIIA-3. Subgroup D contained L. monocytogenes-specific virulece gene inlJ. However, this gene carried a premature stop codon mutation that led to production of a truncated and possibly nonfunctional InlJ due to a non-in-frame deletion of seven nucleotide acids within the 11th PRR. Thus, subgroup D failed to invade and spread efficiently.
Overall, a stepwise evolution model of L. monocytogenes-L. innocua clade was demonstrated. If we consider gene deletion as an important force in Listeria evolution, L. monocytogenes serovar 1/2c (lineageⅡ) is more ancestral in this clade, and evolved in three directions. One evolved into serovar 4b (lineageⅠ) via serovar 1/2b (lineageⅠ); one gave rise toⅢB (fromⅢB-1 toⅢB-2);and the other turned into serovar 1/2a (lineageⅡ) andⅢA-1/2, and the latter further intoⅢC (fromⅢC-1 toⅢC-2) andⅡA-3.ⅢA-3 evolved into L. innocua via subgroup D.
4. Functional genomics of L. monocytogenes under acidic conditions
Based upon the comparison of gene transcription profiling at neutral (pH7.0) and acidic (pH4.8) conditions using Solexa genome analysis system, two systems were identified from the whole genome of 10403S with elevated transcriptional levels under acidic conditions.One was the glutamate decarboxylase (GAD) system, and the other was the putative arginine deiminase (ADI) system (lmo0036-lmo0043 cluster). The GAD system involved three GAD paralogs (gadDl,gadD2, gadD3) located in three distinct loci.The transcription of gadD2 and gadD3 were increased under acidic condition, indicating a role of GAD system in acid tolerance. Moreover, it is suggested that GAD system co-evolved with inlGHE and inlGC2DE.
From perspectives on molecular evolution and functional genomics, ADI gene island is of great interest to us.This island comprised eight genes, arc family genes arcABCD, aguA family genes aguAl and aguA2, one putative transcriptional regulator lmo0041,and one unknown gene lmo0042, which involved in arginine deiminase and agmatine deiminase systems.The transcription of those genes were increased under acidic condition relative to those under neutral condition. The AarcA,ΔarcB,ΔarcD,ΔaguA1 andΔaguA2 null mutants exhibited impaired growth rate under low pH (pH 5.5).Deletion of these genes also led to a decreased survival rates in synthetic human gastric fluid (pH 2.5).In addition, these knock-out mutants demonstrated a lower pathogenicity to mice relative to wild-type strain. Remarkably, aguAl and aguA2 represented two agmatine deiminase (AgDI) paralogs, but AguA2 contributed to acid tolerance and pathogenicity more effectively.
5. Molecular mechanisms of the arginine deiminase-agmatine deiminase system in L. monocytogenes
arcA (lmo0043) encoded ADI using arginine as substrate. L. monocytogenes harbored the whole arg gene family, suggesting arginine could be synthesized de novo. Also, L.monocytogenes was able to uptake extracellular arginine under strong acid conditions.ADI triggered the ADI pathway, and mediated the first reaction producing citrullin and ammonia. aguAl (lmo0038) and aguA2 (lmo0040) encoded two AgDI paralogs with agmatine as substrate.L. monocytogenes was able to produce agmatine from arginine using arginine decarboxylase, and uptake extracellular agmatine under strong acid conditions. AgDI initiated the AgDI pathway, and mediated the first reaction producing carbamoylputrescine and ammonia. Interestingly, although AguAl and AguA2 showed similar hydrophilicity and contained similar active sites, AguA2 played a more important role in acid tolerance.
ArcB (lmo0036) displayed the ornithine carbamoyltransferase (OTC) and putrescine carbamoyltransferase (PTC) activities, representing the first example of carbamoyltransferase responsible for two sets of reversible reactions,in vitro kinetic studies showed that the equilibrium of the reaction lied overwhelmingly towards the formation of citrulline or carbamoylputrescine (anabolic reaction).While the optimum pH for anabolic reactions were at pH 8 to pH 10, the optimum pH for catabolic reactions were at pH 5 to pH 5.5,indicating ArcB possibly served as catabolic OTC or PTC under acidic conditions. While catabolic OTC mediated the reaction yielding ornitine and carbamoyl phosphate, catabolic PTC mediated reaction with the products of putrescine and carbamoyl phosphate. Thus, ArcB linked the second and following reaction steps, and promoted the ADI and AgDI pathways.
Carbamoyl phosphate turned into ammonia, carbon dioxide and ATP by carbamate kinase (CK).Ornithine or putrescine was transported out of the cell in exchange for a molecule of arginine or agmatine by a membrane-bound antiport (AP) encoded by arcD (lmo0037), initiating a new metabolic circle at a state of dynamic equilibrium. For each mole of arginine catabolized via the ADI or AgDI pathway, two moles of ammonia were produced. This ammonia combined with intracellular cytoplasmic protons to yield ammonium inos (NH4+), thereby alleviating acidification of the cytoplasm and maintaining pH homeostasis.
Beneath the exquisite organization of ADI system, it revealed a rigorous transcriptional network. Lmo0041,a rpiR family transcriptional regulator, and ArgR, an arginine biosynthetic repressor, regulated ADI/AgDI pathways negatively and positively in the synthetic human gastric fluid. The repressive function of Lmo0041 took precedence over the activation of the ADI system mediated by ArgR. ArgR also elevated the expression of Lmo0041,which further facilitated its repression of ADI system. PrfA and stress regulator SigB might be at the top of the hierarchy of regulatory network, regulating ADI system as well as ArgR and Lmo0041,evidenced by the potential PrfA and SigB binding sites proceeding the genes in ADI gene island as well as argR.These regulators activated or repressed the ADI system under varied conditions, which mediated listerial acid tolerance and pathogenicity.
In conclusion, this study demonstrated that(1)L. monocytogenes food isolates (except lineageⅢisolate M7) all exhibit virulence potential, among which the isolates from imported aquatic products pose higher risk than those from Chinese food system; (2) L. monocytogenes lineageⅢencompasses a diversity of sublineages, with sublineage IIIA-3 showing low virulence which possibly caused by G145S mutation in PrfA; (3)L. innocua is a young species, and comprises four subgroups, with subgroup A representing the possible evolutionary direction towards adaptation to enviroments, and subgroup D together with L. monocytogenes sublineageⅢA-3 serve as evolutionary intermediates of the L. monocytogenes-L. innocua clade, representing a rare example of evolution towards reduced virulence of pathogens;(4) GAD and ADI systems contribute to the acid stress responses in L. monocytogenes, and ADI system is also involved in the listerial pathogenesis; (5) ADI pathway and AgDI pathway are mediated by functional proteins, including ADI, two paralogs of AgDI, OTC/PTC and AP;and (6) ADI system is under the regulatory network.
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