2023, Vol. 18
结核分枝杆菌(Mycobacterium tuberculosis)是一种极具危害性的兼性细胞内寄生菌。据世界卫生组织(World Health Organization，WHO)报道，全球每年有100多万人死于结核分枝杆菌感染引起的结核病，同时每年有近1 000万新发结核病患者，结核分枝杆菌潜伏感染人群接近20亿[1]。此外，多重耐药结核分枝杆菌的出现和增多，也给结核病的治疗和预防带来了严峻挑战。为此，联合国《2030年可持续发展议程》提出2030年之前要消除结核病，WHO也提出了在2035年“终结结核病”的目标。
结核分枝杆菌的细胞壁主要由具有独特和非典型结构的多糖和脂质组成，约占细胞壁干重的60%[2]，该百分比可能会因物种、分离培养、生长条件不同而异。细胞壁成分可保护结核分枝杆菌免受环境的影响，还能在感染期间调节宿主免疫反应，从而在结核分枝杆菌感染发病机制中发挥重要作用。结核分枝杆菌细胞壁中的脂质成分与其致病能力密切相关，随着脂质含量增多，其毒力增强[3]。此外，在分枝杆菌中发现的各种海藻糖脂、聚酮化合物和大多数其他脂类在非分枝杆菌生物中是不存在的[4]。因此，结核分枝杆菌细胞壁中所包含的糖类、脂质，尤其是糖脂类成分的研究对结核病的诊断、防治具有重要价值。本文针对结核分枝杆菌细胞壁中的部分脂质成分的生物活性作一综述，以期为其相关基础研究提供参考。
1 结核分枝杆菌的细胞壁结构综合目前国际上关于分枝杆菌的细胞壁结构模型，结核分枝杆菌细胞壁的结构如图 1所示，从内向外依次为细胞膜、肽聚糖(peptidoglycan，PG)层、外膜层、荚膜。①细胞膜：结核分枝杆菌具有典型的细菌细胞膜。②PG层：PG与阿拉伯半乳聚糖(arabinogalactan，AG)共价连接，AG在其非还原端酯化为α -烷基、β -羟基长链分枝菌酸(mycolic acid，MA)。③外膜层：结核分枝杆菌外膜是不对称的双层结构[5]，主要由MA和磷脂构成，非共价连接嵌入丰富的脂质和脂多糖，如磷脂酰肌醇甘露糖苷(phosphatidylinositol mannoside，PIM)、结核菌醇二分枝菌酸(phthiocerol dimycocerosate，PDIM)、酚糖脂(phenolic glycolipid，PGL)、海藻糖单霉菌酸酯(trehalose monomycolate，TMM)、海藻糖二霉菌酸酯(trehalose-6, 6’-dimycolate，TDM)、硫脂(sulfolipid，SL)、甘露糖帽修饰的脂阿拉伯甘露聚糖(mannose-capped lipoarabinomannan，ManLAM)，以及各种酰基海藻糖，如二酰基海藻糖(diacyltrehalose，DAT)等。其中，LAM(ManLAM) 通过PIM锚定基因与细菌细胞膜相连接并贯穿细胞壁到达外膜外[6]。外膜为高度不可渗透的不对称双层结构，赋予分枝杆菌对许多治疗药物的特征性抗性[5, 7]。④荚膜：结核分枝杆菌最外层松散附着着主要由α -D-葡聚糖和蛋白质以及少量脂质(占外膜2%~3%)构成的荚膜层。荚膜上还含有D-阿拉伯糖-D-甘露聚糖(D-arabino-D-mannan)等[8]。
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| Many of the classes of (glyco)lipids discussed in the paper are represented schematically and are shown in probable locations in the cell envelope. Light blue stripes represent galactose residues; purple stripes represent arabinose residues; brown stripes represent mannose residues. LM, lipomannan; MA, mycolic acid; ManLAM, mannose-capped lipoarabinomannan; PIM, phosphatidylinositol mannoside; PDIM, phthiocerol dimycocerosate; PGL, phenolic glycolipid; TMM, trehalose monomycolate; TDM, trehalose-6, 6'-dimycolate; SL, sulfolipid; DAT, diacyltrehalose; PAT, polyacyltrehalose. ManLAM was formed by arabinosylation of PIM and connected with bacterial cell membrane through PIM anchored gene and penetrated into outer membrane. 图 1 结核分枝杆菌细胞壁结构 Fig. 1 Schematic diagram of cell wall of Mycobacterium tuberculosis |
MA又称霉菌酸(mycolate)，不仅存在于分枝杆菌属，还存在于诺卡菌属、红球菌属、棒状杆菌属，不同属菌株所含MA的碳链长度不同。MA的整体分子结构已于20世纪60年代后期阐明，结核分枝杆菌中MA的典型结构由α-烷基、β -羟基长链(C60-C90)脂肪酸组成[9]。
结核分枝杆菌具有3大类MA：α -MA(二-顺式环丙烷化)、酮基-MA(α -甲基支化酮和顺式、反式环丙烷化)和甲氧基-MA(甲醚和顺式、反式环丙烷化)[10](见图 2)，以游离形式或酯化成不同糖脂形式存在，如TMM、TDM、葡萄糖单霉菌酸酯(glucose monomycolate，GMM)等[11]。不同类型的MA攻击中性粒细胞、诱导泡沫巨噬细胞(foamy macrophage，FM)或采用抗原结构进行抗体识别的能力不同，受分枝结构中支链、顺式/反式环丙烷和含氧基团的化学功能影响。MA可刺激T细胞产生细胞因子[12-13]，但与CD1d反应性自然杀伤T细胞(natural killer T cell，NKT)表达的保守T细胞受体(T cell receptor，TCR)不同，迄今为止鉴定的MA反应性T细胞克隆表达多种TCR[13]，因此明确MA亚类的特异性可为开发脂质作为疫苗成分和确定结核病患者免疫显性抗原提供新信息。小鼠实验证明，含氧MA是结核分枝杆菌毒力所必需的[14]。有研究比较不同MA组成的分枝杆菌，发现只有具有含氧MA的分枝杆菌才会诱导人类FM的形成，当巨噬细胞被MA诱导成泡沫细胞后，其自身的自噬功能被抑制，这可能是结核分枝杆菌潜伏感染的一个重要因素[15]。同样，α -MA在近端位置的环丙烷化显示会影响“索状”的形成和结核分枝杆菌的毒力[16-17]。
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| Lipids based on their functional groups. MA, mycolic acid; TMM, trehalose mono-mycolate; TDM, trehalose-6, 6’-dimycolate; LM, lipomannan; PDIM, phthiocerol dimycocerosate; PGL, phenolic glycolipid; ManLAM, mannose-capped lipoarabino-mannan; SL, sulfolipid; Ac2SGL, diacylated sulfoglycolipid. 图 2 结核分枝杆菌细胞壁脂质的代表性结构 Fig. 2 Representative structures of Mycobacterium tuberculosis cell wall lipids |
MA在生物膜形成中发挥作用，是一个很好的药物作用靶标。典型的代表是酮基-MA。通过删除mmaA4(或hma)基因所得到的缺乏酮基-MA的结核分枝杆菌突变体，被证明在液态生长条件下具有膜缺陷，对利福平高度敏感[18]。因此，分枝杆菌通过调节生物合成酶的水平和活性来控制MA代谢基因的表达，以满足新膜合成及其复杂细胞壁延伸的需求来适应生存环境[19]。
2.2 TMM与TDMTMM由1个海藻糖和1个长链脂肪酸形成，在TDM和细胞壁形成过程中充当供体。在细胞质中海藻糖首先转化为TMM[20]，然后通过特定的非典型脂质转运蛋白MmpL3.5转运穿过细胞膜，由Ag85(A、B、C)复合物催化TMM转化为TDM[21-22]。因此，抑制TMM转移与乙酰化的化合物是结核分枝杆菌的有效抑制剂。MmpL3作为一种重要的转运蛋白，是最有希望的抗分枝杆菌药理学靶点之一[23]。
TDM由1个海藻糖和2个长链脂肪酸形成，导致结核分枝杆菌呈索状生长，其又称为索状因子(cord factor)，是结核分枝杆菌的重要毒力因子。TDM的生物学活性与溶剂相关。在生理盐水中，TDM是无毒的。当TDM以单分子层存在于脂质微滴表面时，其毒性很强[24-25]。TDM与油的混合物是增强和刺激免疫反应最有效的佐剂[25]。最新研究表明，与脂质相互作用，激活TDM毒性是内源性脂质性肺炎触发干酪样坏死的重要原因[26]。无毒的结核分枝杆菌也具有TDM，但表面游离的量非常少[27]。TDM分子很大，覆盖在细菌表面，不溶于水，可阻止吞噬溶酶体融合和吞噬体酸化，从而阻止结核分枝杆菌被巨噬细胞杀死和抗原呈递[28]。TDM及其衍生物海藻糖二十二酸酯(trehalose-6, 6 ′ -dibehenate，TDB)对具有抗菌功能的γ干扰素(interferon γ，IFN- γ)诱导的基因[包括模式识别受体、主要组织相容性复合体(major histocompatibility complex，MHC)Ⅱ类基因和IFN-γ诱导的GTPase]有延迟抑制作用。TDM通过下调巨噬细胞表面MHC Ⅱ类分子表达以阻止T细胞活化，对IFN- γ诱导的抗原呈递和抗菌基因表达呈负调节，这可能有助于提高结核分枝杆菌感染的持久性[29]。
TDM可刺激机体产生高水平的抗体，因此基于TDM的血清诊断可用于诊断肠结核和眼部结核[30]，抗Ag85B、抗早期分泌抗原靶6(early secreted antigenic target-6，ESAT-6)和抗TDM抗体混合物的检测优于单个抗体的检测[31]。同时，TDM在抗肿瘤[32]、诱导细胞因子[33]、促进血管生成[34]等方面具有重要的研究价值。
2.3 LAMLAM有3部分结构：D-吡喃甘露糖残基、含D-阿拉伯呋喃糖的阿拉伯聚糖、修饰阿拉伯聚糖末端的加帽基序组成的脂化甘露聚糖核心[35]。结核分枝杆菌中的阿拉伯聚糖末端被修饰了由寡甘露糖苷组成的帽子，生成ManLAM(见图 2)。不同类型的结核分枝杆菌核心甘露聚糖和阿拉伯聚糖结构域基本相同，加帽基序的结构和加帽程度因物种而异[35]。脂甘露聚糖(lipomannan，LM)与PIM作为前体进一步阿拉伯糖基化形成LAM，阿拉伯糖基转移酶EmbC参与LAM的合成，并参与结核分枝杆菌活力的维持，诱导EmbC的活力下降，从而减少LAM的合成[36]。
LAM对天然免疫反应具有深远影响，在诱导人类巨噬细胞和树突细胞产生细胞因子方面表现出不同程度的活性[37]。ManLAM与天然免疫细胞上的几种C型凝集素配体相互作用[38]，在结核分枝杆菌感染期间[39]和卡介苗(bacillus Calmette-Guérin，BCG)接种后[40]会诱导产生抗LAM抗体，后者可增强供体巨噬细胞对结核分枝杆菌的摄取和杀伤[41]。
人体血清IgG对LAM及其前体阿拉伯甘露聚糖(arabinomannan，AM)具有特异性，通过抗LAM抗体检测尿液中的LAM，此法填补了急需的简单快速的结核菌检测空白[42]。Ishida团队发现2种新的抗AM/LAM单克隆抗体，可识别不同于其他已报道的抗AM/LAM单克隆抗体识别的聚糖表位，对毒性结核分枝杆菌和非结核分枝杆菌的识别有显著差异，还可检测感染肺中的结核分枝杆菌和LAM[43]。AM及其衍生物阿拉伯甘露聚糖寡糖(arabinomannan oligosaccharide，AMO)与各种载体蛋白(如Ag85B)的结合物是结核分枝杆菌疫苗的候选物[44-45]。
2.4 PDIMPDIM是长链脂质，具有由2个甲基支链脂肪酸长链酯化的苯硫酚核心(见图 2)[46]。最新研究认为，PDIM是结核分枝杆菌被巨噬细胞有效吞噬的关键贡献者，其脂质插入巨噬细胞磷脂双分子层内，诱导细胞膜重组，从而促进吞噬作用[47]。被巨噬细胞摄取后，PDIM参与结核分枝杆菌对吞噬体酸化的调节，阻止吞噬体成熟[47]。有研究发现，与野生株相比，PDIM高表达的突变株感染巨噬细胞期间表现出吞噬体逃逸、自噬和坏死的概率增加，提示PDIM可能参与了巨噬细胞吞噬体逃逸、自噬和细胞凋亡的调节[48-49]。PDIM可能会掩盖细菌病原体相关分子模式(pathogen-associated molecular pattern，PAMP)，导致天然免疫细胞上的Toll样受体(Toll-like receptor，TLR)无法有效识别细菌，从而帮助结核分枝杆菌逃避天然免疫反应[50]。PDIM还与自然或获得性耐药有关。例如，一种PDIM耗尽的海分枝杆菌(Mycobacterium marinum，M. marinum) Δ tesA菌株对利福平、多西环素、环丙沙星和链霉素等抗生素的敏感性增强[51]。
PDIM是结核分枝杆菌维持毒力所必需的成分，但其作用可能是间接的。例如牛分枝杆菌(Mycobacterium bovis，M. bovis)BCG菌株，它的PDIM阳性但无毒。PDIM与众所周知的毒力效应物ESX-1密切相关。有研究发现，分枝杆菌的吞噬体逃逸需要PDIM和ESX-1共同实现[52]。纯化的PDIM本身不具有免疫原性，不会触发免疫反应[53]，但其通过与ESX-1的复杂联系，可促使疾病过程中受感染的巨噬细胞出现I型IFN反应[54]，须进一步研究。
体外传代培养倾向于提高PDIM耗尽细菌的比例[55]，因为PDIM在体外是非必需的，使用固体培养基进行传代可保存PDIM阳性菌株[56]。
2.5 PGL大多数分枝杆菌属细菌会产生PGL，但其结构具有种属特异性。结核分枝杆菌的PGL是基于苯酚硫醇的糖脂，具有与PDIM非常相似的脂肪酸主链[57](见图 2)。PGL可抑制TLR2介导的免疫反应，减少多种促炎细胞因子的产生，如肿瘤坏死因子α (tumor necrosis factor α，TNF- α)、白细胞介素6(interleukin 6，IL-6)、CC趋化因子配体2(C-C motif ligand 2，CCL2)和核因子κ B(nuclear factor κ B，NF- κ B)[58]。此外，PGL能通过CC趋化因子受体2(C-C motif receptor 2，CCR2)招募巨噬细胞，使细菌传播到下呼吸道[59]。如果结核分枝杆菌不能产生PGL，其将分泌大量与生物合成密切相关的聚糖pHBAD，抑制IFN- γ的产生，从而抑制免疫反应[60]。Cambier等[59]研究发现了新的结核分枝杆菌逃逸机制，其使用PGL作为毒力因子来触发有害的CCL2介导的募集信号，细菌不会被常驻巨噬细胞(resident macrophage，RM)破坏，而是通过引导RM将非杀菌单核细胞募集到感染部位来“争取时间”帮助细菌逃逸。PGL与PDIM结构相似，且生物合成均受聚酮合酶(polyketide synthase，PKS)的影响[61]，常将两者并列研究。但PGL具有抗原性，基于PGL-I及其合成模拟物ND-O-BSA的酶联免疫吸附试验(enzyme-linked immunosorbent assay，ELISA)抗体检测被广泛用于多菌型麻风病的诊断[62]。有研究显示，印度尼西亚西爪哇万隆结核病患者血清中抗PGL-I IgG抗体的血清阳性率为41.96%[63]。
2.6 SLSL是一种在硫酸化海藻糖核心上含有4个酰基链的糖脂(见图 2)。20世纪80年代末，有研究证实SL可抑制几种关键宿主细胞对分枝杆菌感染的反应，如巨噬细胞中的溶酶体融合、人中性粒细胞和巨噬细胞的激活，以及细胞因子的产生[64]。但有研究发现，纯化的SL不是经典的促炎刺激物，在多种细胞类型中均未诱导产生TNF[65]。有研究发现，敲除磺基转移酶(sulfotransferase，stf)stf0的结核分枝杆菌突变株无法生成SL-1，但不会损害体外结核分枝杆菌细胞壁的完整性和渗透性；缺乏SL-1的菌株在人类巨噬细胞内的存活率增高，也不影响在鼠巨噬细胞内的存活率；stf0突变株对抗菌肽LL-37具有更强的抵抗力[65]。
此外，一份具有里程碑意义的研究报道了SL新的生物学作用。Shiloh实验室发现，SL-1能够激活存在于肺部的伤害性神经元，并诱发咳嗽[66]，而咳嗽是结核分枝杆菌传播的主要途径。针对SL在结核分枝杆菌发病机制和毒力中的确切作用尚须进一步深入研究。
2.7 SGLSGL是仅在结核分枝杆菌中发现的细胞壁脂质家族，由具有4个不同长度的酰基链的磺基海藻糖核心组成[67]。SGL仅存在于毒力菌株，不存在于模式菌株或疫苗菌株[68]。SGL的合成受PhoP调控[69]。2004年，Gilleron等[70]从结核分枝杆菌中分离出一种新的硫酸化特异性脂质，称为二酰化磺基糖脂(diacylated sulfoglycolipid，Ac2SGL)(见图 2)。其通过CD1b分子诱导T细胞反应，使激活的T细胞释放IFN- γ，同时激活的T细胞能识别结核分枝杆菌感染的抗原呈递细胞，并在体外杀死细胞内驻留的结核分枝杆菌[70]。因此，可利用SGL特异性T细胞研发新的基于脂质的结核病防治策略。
3 结语除上述脂质外，结核分枝杆菌细胞壁中还含有一些因含量较低而研究较少的脂类，如甘油磷酸脂[71]。虽然上述脂质成分目前均可通过化学合成进行体外研究[72]，但分枝杆菌细胞壁的各类成分在生长繁殖阶段是动态变化的。例如，细菌在生长停滞状态下TMM和TDM生成减少[73]，而游离MA水平增加[74]；在营养不足、缺氧状态下PDIM合成减少[75]；体外不同营养条件培养下脂质成分的含量和结构也会发生改变[76]。此外，在感染过程中这些脂质成分之间的相互作用也尚未阐明。结核分枝杆菌的致病机制取决于其具有特异性、动态性和免疫调节性的细胞壁成分，须进一步深入研究这些细胞壁成分，尤其是未知且变化的脂质分子，从而有助于了解其感染机制，发现新的药物靶点、疫苗、佐剂及用于结核病诊断的生物学标记等。
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