2020, Vol. 15
2. 江苏省非编码RNA基础与临床转化重点实验室，江苏 扬州 225009;
3. 江苏省动物重要疫病与人兽共患病防控协同创新中心，扬州大学兽医学院，江苏 扬州 225009;
4. 江苏省人兽共患病学重点实验室，江苏 扬州 225009
2. Jiangsu Key laboratory of integrated traditional Chinese and Western Medicine for prevention and treatment of Senile Diseases, Yangzhou University, Yangzhou 225009, Jiangsu, China;
3. Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China;
4. Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu, China
沙门菌属(Salmonella)是一群寄生在人类和动物肠道中的革兰阴性杆菌，也是重要的食源性病原菌，威胁着人类的生命健康。沙门菌以血清学作为其常用的分型标准，目前全球已发现近2 600种血清型[1]。沙门菌属中伤寒沙门菌和鼠伤寒沙门菌感染率极高，可引起胃肠炎和菌血症等[2, 3]，其中鼠伤寒沙门菌是造成全身感染的主要病原菌[4, 5]。
病原微生物入侵宿主后，宿主依赖细胞表面或者细胞内的模式识别受体(pattern recognition receptor，PRR)识别微生物的病原体相关模式分子(pathogen associated molecular pattern，PAMP)，进而激活下游的信号通路，促进天然免疫细胞的成熟与活化，以启动抗感染免疫应答[6, 7]。宿主对病原微生物的识别是启动免疫应答的第1步，沙门菌进入肠道后，可以被肠道宿主细胞的Toll样受体(Toll-like receptors，TLRs)识别，并产生大量的炎性因子和趋化因子[6]。又如巨噬细胞中的核苷酸结合寡聚化结构域(nucleotide binding oligomerization domain，NOD)样受体(NOD-like receptor，NLRs)在宿主抗沙门菌感染的天然免疫应答中也发挥重要的作用[6]，它与细菌细胞壁表面的肽聚糖(peptidoglycan，PGN)结合后，通过调控Caspase-1的活化，刺激细胞分泌细胞因子抵抗沙门菌的入侵[8]。除了受体，细胞因子白细胞介素22(interleukin，IL-22)和IL-4也在抵抗沙门菌的感染中发挥重要作用[9]。
虽然天然免疫应答对于宿主抵御沙门菌的感染具有重要的作用，但是沙门菌也演化出一系列逃逸宿主天然免疫应答的策略，使其在宿主体内定植并持续感染宿主细胞。本文对近年来沙门菌通过受体、细胞因子和哺乳动物西罗莫司(又称雷帕霉素)靶蛋白(mammalian target of rapamycin, mTOR)信号通路等逃逸宿主天然免疫应答的研究进展进行综述，期望对沙门菌的防治提供参考。
1 受体介导沙门菌逃逸天然免疫应答机制 1.1 TLRsTLRs是一类分布在细胞膜或者细胞质中能够特异性识别PAMP和损伤相关分子模式(damage-associated molecular pattern，DAMP)的受体，该受体与配体结合后，能够刺激下游信号转导分子和诱导效应炎性介质的表达，并在天然免疫应答与获得性免疫应答之间发挥桥梁作用[10]。每种TLRs都有对应的配体，例如：TLR2和TLR4的配体分别是脂磷壁酸(lipoteichoicacid, LTA)和脂多糖。TLRs与配体结合后，诱导细胞因子的分泌，但是沙门菌会演化出一系列的策略逃逸TLRs所引起的天然免疫应答。研究发现，伤寒沙门菌的沙门菌毒力岛7(Salmonella pathogenicity island 7，SPI-7)编码一些重要的毒力因子，阻止脂多糖与TLR4结合，抑制炎症应答[11]。Arpaia等人通过荧光素酶标记发现TLR2、4、9可能对伤寒沙门菌的识别具有一定作用，进一步构建TLR2×9、TLR4×9和TLR2×4×9敲除小鼠模型，并口服给予伤寒沙门菌后，发现TLR2×9和TLR4×9敲除小鼠更易感，表明某些TLR的存在可以显著提高宿主对伤寒沙门菌的抵抗力[12]。但是TLR2×4×9敲除后伤寒沙门菌对小鼠的感染力显著下降，通过进一步的机制解析，发现该菌被巨噬细胞吞噬后包裹在沙门菌液泡(Salmonella-containing vacuole，SCV)中[13]，伤寒沙门菌表面的PAMP与巨噬细胞的TLR2、TLR4和TLR9同时结合后可诱导SCV酸化，该酸化进一步诱导沙门菌毒力岛2(Salmonella pathogenicity island 2，SPI-2)基因的表达[14]，通过SPI-2介导的3型分泌系统(Type Ⅲ secretion system，T3SS-2)分泌效应蛋白到达胞质，有利于伤寒沙门菌在SCV中的存活与复制，巨噬细胞缺乏TLR2、TLR4和TLR9后，SCV则无法酸化，伤寒沙门菌无法存活和复制[12]。由此发现，TLRs与配体结合，可以启动下游信号通路，诱导炎症因子的产生，发挥抗伤寒沙门菌的作用，但是有些伤寒沙门菌通过抑制TLRs与配体的结合，抑制炎症因子的产生，还有些伤寒沙门菌利用TLRs与配体的结合，诱导SCV酸化，有利于伤寒沙门菌的感染[12]。同时有研究发现，肠炎沙门菌中含有Toll/interleukin-1 (IL-1) receptor(TIR)结构域的基因TcpS，肠炎沙门菌通过T3SS-1分泌TcpS蛋白，TcpS可以模拟TLRs的TIR结构域干扰TLR-NF-κB信号通路，抑制p65的入核以及炎性细胞因子的分泌，从而逃逸天然免疫应答[15]。
1.2 NLRsNLRs是细胞内PRRs中的一个大家族，根据功能可将NLRs家族成员分为两组。一组包括NOD1和NOD2，它们可以激活各种转录因子如NF-κB、MAPK和IRFs，诱导促炎细胞因子、抗菌肽和干扰素(interferon, IFN)产生[16]; 另一组包括NLRP3、NLRC4和NLRP6炎性小体等，它们通过调控Caspase-1诱导IL-1家族细胞因子的分泌[17]。宿主感染鼠伤寒沙门菌后，NLRC4和NLRP3均被激活，且与配体结合后诱导Caspase-1活化，促进细胞因子IL-1β和IL-18的分泌，诱导细胞凋亡[18]。NLRC4的配体是鞭毛蛋白，而NLRP3的配体还不是很清楚。与野生型小鼠相比，鼠伤寒沙门菌感染NLRC4和NLRP3敲除小鼠后，肠系膜淋巴结、脾脏和肝脏中的细菌载量显著增多，表明NLRC4和NLRP3在抗鼠伤寒沙门菌感染中发挥重要作用。研究发现，活性氧(reactive oxygen species，ROS)可以引起K+外排，进而诱导NLRP3炎性小体的活化[19]，而鼠伤寒沙门菌通过调控三羧酸循环中所需要的两种酶(顺乌头酸酶和异柠檬酸脱氢酶)减少细胞ROS的产生，抑制NLRP3炎性小体的活化和细胞因子的分泌，增强对小鼠的感染能力[20]。与NLRC4和NLRP3功能相反，NLRP6和NLRP12的活化与鼠伤寒沙门菌的易感性呈正相关。与野生型小鼠对比，鼠伤寒沙门菌感染NLRP6和NLRP12敲除小鼠后，肝脏和脾脏中细菌载量显著下降，单核细胞和中性粒细胞的数量显著增多，NF-κB信号通路得到了显著激活。该结果表明，鼠伤寒沙门菌通过诱导NLRP6和NLRP12的活化负向调控炎症应答以实现免疫逃逸，使鼠伤寒沙门菌更好地在宿主细胞内复制，并最终增强其对宿主的感染能力[21]。
1.3 RIPs受体相互作用蛋白(receptor interacting proteins，RIPs)是丝氨酸/苏氨酸蛋白激酶家族中的重要成员，RIP3和RIP1的C端均存在着相互作用基序，所以可以形成RIP1-RIP3复合体[22]。研究发现，肠炎沙门菌感染宿主后，通过调控IFN诱导RIP1和RIP3活化形成RIP1-RIP3复合体，促使RIP1磷酸化[23]，抑制NF-κB的活化[24]。此外，肠炎沙门菌感染巨噬细胞后，通过提高RIP3的表达诱导RIP1磷酸化，引起巨噬细胞坏死性凋亡[23]。肠炎沙门菌感染RIP3敲除小鼠后，宿主内F4/80+ CD11b+巨噬细胞的数量显著增多，凋亡的巨噬细胞数量显著下降，将RIP3敲除小鼠的F4/80+ CD11b+巨噬细胞过继回输到野生型小鼠体内，可以显著提高野生型小鼠抗肠炎沙门菌感染的能力[23]。综上所述，肠炎沙门菌可以通过激活RIP1和RIP3，一方面抑制NF-κB的活化，另一方面诱导巨噬细胞凋亡，进而逃逸宿主免疫应答，增强其在宿主体内的增殖能力。
2 细胞因子介导沙门菌逃逸天然免疫应答机制 2.1 IL-22IL-22是IL-10家族中的一员，主要由淋巴细胞产生，如辅助T(helper T，Th)17细胞、Th22细胞等。细菌感染宿主后，巨噬细胞分泌的IL-18可诱导Th1细胞释放IFN-γ[24]，树突细胞和其他单核细胞分泌的IL-23可诱导多种免疫细胞产生促炎细胞因子IL-17和IL-22[25]，以提高肠道上皮细胞和中性粒细胞内抗菌蛋白的表达，主要包括金属螯合脂质运载蛋白-2(lipocalin-2)和钙卫蛋白(calprotectin)[26, 27]，这两种蛋白能够抑制非伤寒沙门菌利用肠道中的金属离子，使其缺乏必要的微量营养物质。lipocalin-2可以阻止细菌释放的铁载体与肠道中的铁结合[28]，calprotectin可以通过螯合锌离子和锰离子来发挥其抗微生物的作用[29]。虽然宿主通过分泌抗菌蛋白限制病原微生物与多种对代谢功能至关重要的金属离子的结合，抑制病原微生物增殖，但对于非伤寒沙门菌却有相反的效果。首先，非伤寒沙门菌表达修饰的铁载体不受lipocalin-2的束缚，因此即使细胞产生了lipocalin-2，非伤寒沙门菌也能够获得铁[30]。其次，非伤寒沙门菌具有高亲和力的锌转运蛋白，在calprotectin存在的前提下，依旧可以获得锌[26, 27]。此外，这些机制不仅可以帮助非伤寒沙门菌逃逸肠道免疫应答，同时也提高了非伤寒沙门菌与肠道其他菌群的竞争优势。研究发现，IL-22会显著提高宿主内lipocalin-2和calprotectin的表达水平，非伤寒沙门菌感染IL-22敲除小鼠后，该菌丧失了与肠道菌群竞争的优势，所以很快被宿主免疫系统清除[27]。由此可见，IL-22诱导的肠道内多种抗菌蛋白的表达虽然不会影响非伤寒沙门菌对铁、锌等营养物质的获取，但可以增加非伤寒沙门菌与肠道菌群的竞争优势，使其在逃逸宿主免疫应答的同时，更好地在宿主体内复制与定植。
2.2 IL-4IL-4由Th2细胞分泌，可以刺激B细胞活化和T细胞增殖，在调节适应性免疫应答中发挥重要的作用[31]。依据所分泌的细胞因子和生物学功能，将Th细胞分为Th1和Th2细胞。Th1细胞主要分泌IFN-γ和TNF-α等细胞因子; Th2细胞主要分泌IL-4、IL-6和IL-10等[32]。研究发现，采用腹腔注射氢化可的松造成小鼠免疫抑制后再接种鼠伤寒沙门菌，小鼠体内IL-4高表达，同时引起过度的Th2型应答，不利于宿主清除细菌[33]。同时也有研究表明，与野生型小鼠对比，IL-4敲除小鼠对鼠伤寒沙门菌的易感性显著下降，且无明显的肝脏损伤[34]。综上所述，IL-4的产生不利于宿主清除沙门菌。
3 mTOR信号通路介导沙门菌逃逸天然免疫应答机制mTOR是一种非典型丝氨酸/苏氨酸蛋白激酶，在哺乳动物中mTOR与不同的蛋白相结合，会形成两种复合物，分别为mTOR复合物1(mTOR complex 1，mTORC1)和mTOR复合物2(mTOR complex 2，mTORC2)[35]。mTORC1可以促进蛋白质合成翻译等代谢过程，并在高营养条件下有效抑制细胞自噬[34]。在天然免疫中，细胞自噬可以调节细胞因子的产生、细菌的降解以及树突细胞诱导的适应性免疫应答。细胞自噬的发生和发展受到多种信号分子的调控，包括磷脂酰肌醇-3-激酶(phosphatidylinositol-3-kinase, PI3K)、蛋白激酶B(protein kinase B，PKB)和mTOR信号通路等。其中，mTOR信号通路最为重要，属于信号转导分子，能接受来自Akt、腺苷一磷酸(adenosine monophosphate，AMP)等分子的信号传递，直接参与细胞自噬的发生和发展[36]。病原菌可以通过激活mTOR途径调节细胞自噬，如鼠伤寒沙门菌表达的天冬酰胺酶[37]，可以持续激活mTOR信号通路从而抑制自噬，降低T细胞活化能力，逃逸宿主免疫应答[38, 39]。
此外，在巨噬细胞和树突细胞中，糖代谢的发生与mTOR激活的缺氧诱导因子-1α(hypoxia inducible factor-1α，HIF-1α)相关[40]。鼠伤寒沙门菌可以通过消耗细胞内葡萄糖调节mTOR激活的HIF-1α，抑制小鼠骨髓基质细胞中糖酵解的发生[41]，巨噬细胞因无法进行糖酵解而死亡，鼠伤寒沙门菌得以逃逸宿主免疫应答[42]。
4 结语宿主免疫应答的激活能够限制鼠伤寒沙门菌等的增殖和传播，然而为了在宿主细胞内增殖，该类细菌也演化出一系列逃逸宿主天然免疫应答的策略，包括逃避TLRs、NLRs和RIPs等受体的识别，促进细胞因子IL-22的分泌以增强沙门菌与肠道菌群的竞争优势，利用IL-4抑制宿主对沙门菌的清除，通过调控mTOR信号通路逃逸宿主天然免疫应答等。因此，更深入地了解沙门菌逃逸宿主天然免疫应答的机制，将有助于指导沙门菌病的预防和治疗。
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