微生物学报  2023, Vol. 63 Issue (9): 3374-3385   DOI: 10.13343/j.cnki.wsxb.20230016.
http://dx.doi.org/10.13343/j.cnki.wsxb.20230016
中国科学院微生物研究所，中国微生物学会

文章信息

陈喆, 田振振, 宋银宏. 2023
CHEN Zhe, TIAN Zhenzhen, SONG Yinhong.
细菌感染与胸腺结构和功能变化的研究进展
Research progress in thymus changes induced by bacterial infections
微生物学报, 63(9): 3374-3385
Acta Microbiologica Sinica, 63(9): 3374-3385

文章历史

收稿日期：2023-01-07
网络出版日期：2023-06-03
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引用本文
陈喆, 田振振, 宋银宏. 细菌感染与胸腺结构和功能变化的研究进展[J]. 微生物学报, 2023, 63(9): 3374-3385.
Chen Zhe, Tian Zhenzhen, Song Yinhong. Research progress in thymus changes induced by bacterial infections[J]. Acta Microbiologica Sinica, 2023, 63(9): 3374-3385.
细菌感染与胸腺结构和功能变化的研究进展
陈喆1,2,3 , 田振振1,2,3 , 宋银宏1,2,3     
1. 肿瘤微环境与免疫治疗湖北省重点实验室(三峡大学), 湖北 宜昌 443002;
2. 三峡大学感染与炎症损伤研究所, 湖北 宜昌 443002;
3. 三峡大学基础医学院, 湖北 宜昌 443002
收稿日期：2023-01-07；接受日期：2023-05-31；网络出版日期：2023-06-03
基金项目：国家自然科学基金(81671397)；湖北省卫健委重点项目(WJ2019H528)
摘要：胸腺是负责T细胞发育分化成熟的中枢免疫器官，除了增龄性胸腺衰退，临床放疗及化疗、感染及肿瘤等因素也是导致胸腺变化的重要原因，胸腺变化包括胸腺结构，胸腺细胞数量与组成以及胸腺功能的变化。本文着重对细菌感染导致的胸腺变化及其相应机制进行综述，并对减轻感染引起的胸腺损伤的策略进行小结，以期为预防或逆转感染引起的胸腺损伤提供一定的临床参考。
关键词：细菌    感染    胸腺    T细胞发育    
Research progress in thymus changes induced by bacterial infections
CHEN Zhe1,2,3 , TIAN Zhenzhen1,2,3 , SONG Yinhong1,2,3     
1. Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, Hubei, China;
2. Institute of Infection and Inflammation, China Three Gorges University, Yichang 443002, Hubei, China;
3. College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, Hubei, China
Received: 7 January 2023; Accepted: 31 May 2023; Published online: 3 June 2023
*Corresponding author: SONG Yinhong, E-mail: syh728@126.com.
Foundation item: This work was supported by the National Natural Science Foundation of China (81671397) and the Key Project of Health Commission of Hubei Province (WJ2019H528)
Abstract: The thymus is the central immune organ responsible for the development, differentiation, and maturation of T cells. In addition to age-related factors, radiotherapy, chemotherapy, infections, and tumors are also major factors for the structure, cellularity, and function changes of the thymus. Here, we introduce the thymus changes induced by bacterial infections and the underlying mechanisms and summarize the therapies for ameliorating infection-associated thymus injuries, aiming to provide references for preventing or repairing infection-induced thymus injuries in clinical practice.
Keywords: bacteria    infection    thymus    development of T cells    

T细胞是机体免疫系统中负责细胞免疫的淋巴细胞，胸腺是负责T细胞发育分化成熟的中枢免疫器官，结构上分为胸腺皮质(thymic cortex)、髓质(thymic medulla)和皮髓质交界处(cortico-medullary junction, CMJ)。胸腺内的淋巴细胞称为胸腺细胞，来源于骨髓的早期胸腺祖细胞(early T lineage precursor, ETP)进入CMJ后，在胸腺上皮细胞(thymic epithelial cell, TECs)等基质细胞的抚育下，首先在皮质分化为双阴性(double negative, DN)细胞，并历经DN1、DN2、DN3和DN4这4个阶段，随后分化为未成熟单阳性(immature single positive, ISP)细胞，紧接着进入双阳性(double positive, DP)细胞阶段，历经DP1、DP2和DP3后通过阳性选择分化为单阳性(single positive, SP)细胞，SP细胞再经阴性选择成为成熟的T细胞，随后迁出胸腺进入外周，从而发挥识别、应答和清除病原体的作用[1]。生理上，胸腺会发生增龄性萎缩[2]。在应激、营养不良、感染和癌症等情况下胸腺也会发生变化[3]。其中细菌感染后胸腺会发生一系列变化，包括胸腺萎缩、胸腺细胞亚群比例及数量等方面(图 1)。针对细菌感染引起的临床疾病，从胸腺的恢复和T细胞再生的角度来着手治疗，可减轻发病率和死亡率[4]。因此，本文对常见细菌感染引起的胸腺变化进行归纳，并对感染导致胸腺变化的机制以及应对措施进行综述。

图 1 细菌感染导致胸腺变化 Figure 1 Characteristics of thymus changes caused by bacterial infections.
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1 引起胸腺变化的常见细菌种类 1.1 革兰氏阴性菌

迄今为止，据文献报道，感染机体后引起胸腺结构及功能变化的革兰氏阴性菌主要有沙门菌、大肠埃希菌、耶尔森菌、克雷伯菌、土拉弗朗西斯菌和铜绿假单胞菌等。脂多糖(lipopolysaccharide, LPS)是革兰氏阴性菌共有的致病物质，它是革兰氏阴性菌细胞壁组成成分，随着细菌死亡裂解而释放。单独用LPS作用于不同的动物，均会使胸腺质量下降，胸腺内DN及DP数量下降，胸腺功能受损[5-7]。但各种细菌由于在生长特性及毒力方面有所区别，感染后造成胸腺结构及功能的变化也有不同，现分述如下：

沙门菌属主要通过人类和动物肠道感染，其中感染率较高的血清型为鼠伤寒沙门菌(Salmonella typhimurium, S. Typhimurium)。腹腔注射S. Typhimurium至小鼠体内，48 h在胸腺发现细菌负荷，一周后胸腺质量和胸腺细胞总数开始降低，在第3周降到最低，减少的胸腺细胞亚群中以DP为主，DN1中ETP比例未变化，感染之前大部分的CD4+SP细胞为未成熟表型，而感染后21 d情况逆转，且次级淋巴器官中胸腺近期迁出细胞(recent thymic emigrant, RTE)数量并未受到较大干扰，此过程中胸腺结构未发生改变[5]。T细胞受体(T cell receptor, TCR)-Vβ8链的DP细胞的百分比在感染期间增加，有利于特定CD4+和CD8+SP细胞克隆的产生[8]。这说明S. Typhimurium感染引起胸腺变化的同时并不影响ETP增殖能力、CD4+SP的成熟以及向次级淋巴组织的迁移能力。另一个雏鸡感染模型也观察到了类似的结果[6]。

另有试验通过口腔感染S. Typhimurium，第2天发现小鼠胸腺有细菌负荷，且胸腺细胞总数降低，其中也以DP为主，但DN、SP的比例相对增加，DN细胞亚群中只有DN1的百分比增加，数量不变，所以感染虽然导致胸腺总细胞数减少，但各阶段细胞亚群数量却略有差异[9]。随着感染的S. Typhimurium剂量增大，胸腺细胞数量减少加剧[10]。其他品系的小鼠感染S. Typhimurium也出现胸腺变化，SvJ小鼠感染后第15天DP数量明显下降[11]。CC042的基因异质性小鼠感染后，胸腺质量下降，DN、DP细胞数量减少，且淋巴造血祖细胞有差异[12]。切除胸腺的C57BL/6J和129x1/SvJ产生的F1杂交小鼠口腔感染后，小鼠全身细菌负荷和死亡率随时间推移显著增加，虽然S. Typhimurium特异性CD4+ T细胞的数量增加，但产生IL-17能力受损，这说明在感染早期，胸腺及其细胞输出在保护性免疫反应中至关重要[13]。

上述均为活菌感染机体引起的胸腺变化，而当同样剂量的热灭活的S. Typhimurium腹腔感染小鼠后，其胸腺重量和细胞数等都无明显改变[5]，即使提高热灭活菌的剂量，胸腺质量和细胞总数也无明显变化[10]。另外将S. Typhimurium通过足部注射小鼠，建立局部感染模型，结果表明胸腺并未变化[5]。因为腹腔、口腔及静脉感染均属于全身感染，并且导致的胸腺变化基本一致，说明胸腺变化主要由活菌造成的全身感染所导致。

大肠埃希菌(Escherichia coli, E. coli)属于条件致病菌。对雏鸡皮下注射E. coli后第1天胸腺DP细胞数量减少，其比例降到85%[14]。腹腔或者静脉注射来自E. coli的LPS后，小鼠胸腺质量下降明显，DP数量减少，但7 d后恢复[15-16]。而提高E. coli来源的LPS剂量后，除了DP、DN减少外，SP胸腺细胞数也显著降低，且ETPs缺失，CMJ也消失[17]。这说明LPS引起胸腺结构及功能的变化与其剂量高度相关。

耶尔森菌(Yersinia)为球杆菌，无胸腺的C57BL/6与BALB/c杂交的F1代小鼠对小肠结肠炎耶尔森菌(Yersinia enterocolitica, Y. enterocolitica)易感，而正常C57BL/6与BALB/c杂交的F1代却有正常的抗感染能力[18]，说明胸腺在机体抗菌能力中起到了至关重要的作用。腹腔注射Y. enterocolitica至C3H/HeJ小鼠后，第1天胸腺发生萎缩，DP细胞明显减少，且TCR-αβ细胞百分比升高[19]，这说明胸腺遭遇细菌感染后T细胞能正确识别外来抗原。通过将鼠疫耶尔森菌(Y. pestis)的V抗原或其V抗原肽lcrV68-326分别与正常人胸腺细胞共培养，发现两者均可与结合在胸腺细胞上的人干扰素-γ (IFN-γ)相互作用，导致正常的原代胸腺细胞凋亡[20]。这是一例细菌感染人胸腺细胞的模型，说明了细菌抗原与胸腺变化关系密切。

同属于革兰阴性细菌的肺炎克雷伯菌(Klebsiella pneumoniae, K. pneumoniae)[21-22]、土拉弗朗西斯菌(Francisella tularensis, F. tularensis)[23-24]及铜绿假单胞菌(Pseudomonas aeruginosa, P. Aeruginosa)[25]感染动物也均会造成胸腺质量降低，胸腺细胞分化能力严重下降。另有试验用热灭活P. Aeruginosa皮下注射小鼠后发现，CD4‒胸腺细胞比例增加，CD4+胸腺细胞比例不变。热灭活P. Aeruginosa与来自P. Aeruginosa的LPS两者都使胸腺细胞的细胞因子白介素IL-1β、IL-6和IL-17水平升高，将P. Aeruginosa的凝集素皮下注射24 h后，小鼠胸腺IL-17含量也显著增加[25]。固有免疫细胞在炎性细胞因子驱动下可分泌IL-17，由此可知，细菌感染后炎症细胞因子增多，加剧了胸腺炎症环境，进一步加速了胸腺细胞凋亡，促进胸腺萎缩。

由上述可以看出，革兰氏阴性菌细胞壁固有成分LPS属于病原相关分子模式，游离的LPS可直接与免疫细胞表面的相应受体结合，而完整活菌或灭活菌进入机体内后须裂解才能释放出LPS，因此直接用一定剂量的LPS往往产生更迅速的胸腺变化。另外，由于各种革兰氏阴性菌的生长特性及毒力有所区别，尽管感染机体后均会引起胸腺的变化，但发生变化的时间点以及严重程度也有所不同。

1.2 革兰氏阳性菌

感染后引起胸腺结构和功能变化的革兰氏阳性菌主要有分枝杆菌、单增李斯特菌及链球菌等。不同革兰氏阳性菌具有磷壁酸等共同抗原，但同时也会产生毒力各异的外毒素。这导致不同的革兰氏阳性菌感染机体后会引起胸腺一些相似的改变，但也有其各自的特点。

结核分枝杆菌(Mycobacterium tuberculosis, M. tuberculosis)是引起结核病的主要病原菌。鸟分枝杆菌(Mycobacterium avium, M. avium)属于非结核分枝杆菌，可导致人类慢性肺部疾病。M. tuberculosis感染小鼠3个月后，胸腺是细菌负荷最大的器官，且维持较长时间[26]。将来自分枝杆菌属中7种细菌的致病物质6,6-双分枝菌酸海藻糖(trehalose 6,6'-dimycolate, TDM)静脉注射小鼠7 d后，M. tuberculosis H37Rv和M. kansasii的TDM组的胸腺指数下降最显著，且胸腺皮质层淋巴细胞凋亡[27]。这表明胸腺萎缩的程度因分枝杆菌TDM结构而有所差异。另外，高毒力M. avium感染后，小鼠胸腺重量下降，结构上皮质区域缩小伴CMJ模糊，TECs支持胸腺细胞分化的能力受损，胸腺细胞总数减少，其中DP为主，且引发了外周淋巴细胞减少症[28-29]。低毒力M. avium感染小鼠后并不导致小鼠胸腺萎缩，发现细菌聚集在CMJ和髓质内，但其分化的T细胞在外周器官中抗感染能力受损[28, 30]。M. tuberculosis感染后，胸腺来源的M. tuberculosis特异性调节性T细胞(regulatory T cells, Tregs)数量在3周内达到峰值，随后下降，这有利于平衡M. tuberculosis感染导致的过度炎症反应[31]。

单增李斯特菌(Listeria monocytogenes, L. monocytogenes)感染机体后可增加获得性免疫缺陷胸腺瘤的发生率[32]。小鼠腹腔感染L. monocytogenes后胸腺细胞总数减少，胸腺细胞表面黏附分子Thy-1水平上升，使胸腺细胞与胸腺基质细胞黏附增强，影响胸腺细胞在胸腺内的发育[33]。另有研究发现将M. tuberculosis分泌性蛋白ESAT-6表位(Lm-ESAT-6)的重组L. monocytogenes菌株经肺部感染小鼠后并未引起胸腺来源的L. monocytogenes特异Tregs数量的改变[31]。

猪链球菌2型(Streptococcus suis, S. suis)是一种新出现的人畜共患病原体[34]。S. suis注射小鼠后胸腺会迅速萎缩[35]。化脓性链球菌(Streptococcus pyogenes, S. pyogenes)感染小鼠后胸腺细胞总数显著降低，第4天降到最低，其中以DP为主，DN、SP细胞百分比相对增加，同时在感染第2天Treg细胞的百分比显著增加[36]。

由上述可知，各种细菌引起的胸腺变化特征既有相似性，也有一定差异(表 1)。胸腺变化主要包括胸腺结构紊乱、细胞数量减少、胸腺功能减退，同时胸腺变化也包括细胞因子分泌水平的改变。细胞变化主要表现为未成熟胸腺细胞的凋亡，尤其是DP细胞，但对即将迁移出胸腺发挥抗菌感染的SP细胞影响较小，仅表现为成熟延迟等，同时也影响到TEC分化[29, 35]。高剂量、高毒力菌株感染后诱导胸腺质量下降、胸腺细胞数凋亡等胸腺的实质性改变，低毒力和低剂量往往导致慢性感染，对胸腺影响较小，且短时间内能够恢复，同时降低细菌感染量后小鼠胸腺细胞数也会恢复，这可能与早期胸腺祖细胞的比例和增殖有关[5-6, 16]。

表 1. 不同细菌感染导致胸腺变化特征和机制 Table 1. Characteristics and mechanisms of thymus changes caused by different bacterial infections
Bacteria Dose Route Strain Model Characteristics of thymus changes Mechanism Reference
S. Typhimurium 5×105 CFU i.p. i.v. SL3261 C57BL/6 Mass↓ Thymocyte ↓ DP ↓↓ SP ↓ Structure unchanged FOS/JUN↑ IL-8, CCL4↑ DNA damage Cell cycle arrest [5]
H.K (5×105 CFU) s.c. i.p. SL3261 Thymocyte unchanged
5×105 CFU i.p. SL1344 Mass↓Thymocyte↓↓
50 CFU 500 CFU i.p. 14028 Bacterial load unchanged Structure disorder Thymocyte↓ DN↓ TCR-Vβ8+DP ratio↑ NA [8]
5×104 CFU i.p. cvcc541 Chick Cobb 500 Thymus index↓ Cortical thymocyte↓ TLR4-FOS/JUN↑ Inflammatory response↑DNAdamage [6]
108 CFU Orally NCTC 12023 C57BL/6 ISP↓↓DP1↓DP2↓DN3↓DN4↓DN2↓ GC↑ IFN-γ↑ [9]
108 CFU Orally NCTC 12023 C57BL/6 Bacterial load↑ Thymocyte↓ DP↓↓ Cortisol↑IFN-γ↑ Independent of Fas/FasL [10]
H.K (109, 1010 CFU) Orally NCTC 12023 C57BL/6 Thymocyte unchanged
109 CFU Orally NCTC 12023 BALB/c Thymocyte↓ ↓ DP↓ DN2-4↓↓ DN1 unchanged NA [7]
E. coli 104, 105 CFU s.c. Isolated from turkey with septicemia Chick DP↓ NA [14]
Y. enterocolitica 80 μg SN i.p. ATCC 23715 C3H/HeJ DP↓ αβ T cells↑ NA [19]
NA NA LcrV Thymocyte Thymocyte apoptosis Interacts with hIFN-γ binding to thymocyte [20]
K. pneumoniae 4×106 CFU i.p. C3H/HeN C3WHeJ C57BL/6 Mass↓ Thymocyte↓↓ TNF-α↑ [21]
NA NA 5215777 Calf Collagen fibers in cortex↑ Cortical thymocyte↓ NA [22]
F. tularensis 103 CFU i.p. SCHU S4 BALB/c Mass↓ Cortical thymocyte↓↓ NA [23]
10‒20 CFU Aerosol FSC033/ snMF C57BL/6 Thymus differentiation ability↓ Cortical layer thickness↓ DP↓ Co-regulation of corticosteroid and TNF-a [24]
P. Aeruginosa H.K. (106‒107 CFU) s.c. HKPA C57BL/6 BALB/c CD4-Thymocyte ratio↑ CD4+Thymocyte ratio unchanged IL-1β, IL-6, IL-17↑ NA [25]
M. tuberculosis 75 CFU Aerosol H37Rv C57BL/6 Bacterial load↑ naïve CD4+ T↓RTEs↑ IFN-γ↑TNF-α↑ NA [26]
50‒100 CFU Aerosol H37Rv C57BL/6 M. tuberculosis-specific Tregs increased and then decreased IL-12 upregulates T-bet to promote the conversion of CD4+T into Th1 cells [31]
300 μg TDM i.v. H37Rv BALB/c Thymus index↓Cortical thymocyte↓ High toxicity [27]
M. avium 106 CFU i.v. 25291/2447 C57BL/6 Bacterial load↑ Mass↓structure disorder Thymocyte↓↓↓DP↓↓ GC↑ NO↑ [28-29]
106 CFU i.v. 2447 C57BL/6 Bacterial load↑ Antibacteria immunity↓ NA [30]
L. monocytogenes 106 CFU i.v. Lm-ESAT-6 C57BL/6 Tregs unchanged NA [31]
2×104 CFU i.p. EGD BALB/c Thymocyte↓ Thy-1↑ The adhesion of thymocyte to stromal cells was enhanced [33]
S. suis 5×107 CFU i.p. 700794 C57BL/6 DP↓SP ratio↑ thymus returned to normal after 14 hours IL-2, IL-6, IL-12, TNF↑ p53 and Caspase-dependent pathways [35]
S. pyogenes 108‒109 CFU s.c. M49-16 C57BL/6 Thymocyte↓ DP↓DN↑ SP ratio↑ Tregs ratio↑ l-arginine↓ Dysregulation of mTOR induces immunosuppression [36]
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2 细菌感染引起胸腺变化的机制

细菌感染引起胸腺变化并不是细菌和胸腺细胞直接相互作用的结果，其相关机制主要集中在激素、炎症因子、信号通路等因素。

2.1 激素与炎症因子

糖皮质激素(glucocorticoid, GC)可诱导胸腺退化[37]。细菌感染小鼠时血清皮质醇量、GC水平升高，皮质酮浓度略有增加[10, 28]。感染高毒力M. avium后的胸腺细胞在感染期间对GC类药物-地塞米松诱导的死亡的易感性增加[28]。胸腺细胞中促炎细胞因子白介素IL-6、IL-17和肿瘤坏死因子(tumor necrosis factor, TNF)升高[25, 35]。IFN-γ的分泌增多与胸腺细胞减少相关，同时也影响胸腺细胞成熟[9, 29]。感染后外周T细胞可回迁到胸腺可分泌IFN-γ[38]。IFN-γ进一步激活巨噬细胞产生炎症重要的信号分子一氧化氮(NO)和一氧化氮合成酶(inducible nitric oxide synthase, iNOS)从而导致胸腺变化[28-29, 38]。胸腺M. tuberculosis特异性Treg细胞在胸腺发生炎症后快速增加，随后抗炎因子IL-12上调CD4+T、CD8+T细胞的T-bet，从而促进其转化为Th1细胞就使特异性Treg细胞减少，这有利于在感染中后期发挥细胞免疫的作用，促进胸腺的恢复[31]。GC和IFN-γ也可共同导致胸腺细胞死亡数量增加、DP凋亡[10-11]。另一感染模型中皮质类固醇激素和TNF也同时升高[24]。有研究证明NO与GC协同作用影响了骨髓T细胞前体和胸腺T细胞的分化[29]。但有研究发现当减毒细菌感染后，胸腺变化既不依赖于内源性GC的调节，也不依赖于IFN-γ[5]。这可能与细菌不同性质相关，其具体机制还需进一步探索。

2.2 细胞信号通路的激活

上述因素都会触及细胞信号通路，引起下游的一系列反应。

2.2.1 细胞凋亡信号激活

DP细胞中c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)磷酸化水平升高，促细胞凋亡分子上调，同时JNK反馈调节，进一步提高机体炎症水平，更易诱导胸腺萎缩变化[11]。胸腺细胞减少涉及膜去极化和半胱天冬酶3 (caspase-3)激活的凋亡机制[10]。抑癌基因p53和caspase依赖性途径诱导胸腺细胞凋亡[35]。但也有研究发现胸腺细胞减少并不与caspase-3激活相关[29]，Fas/FasL途径也未参与[10]。DP3细胞数量在感染后未发生变化可能归因于抑制细胞凋亡的B淋巴细胞瘤-2基因(B-cell lymphoma-2, Bcl2)在DP3细胞中表达量升高[9]。CCL4的增加会导致胸腺细胞凋亡[6]。LPS引起胸腺变化的原因在于LPS与胸腺表面的TLR4蛋白结合激活转录因子FOS/JUN，从而诱导IL-8、IL-2的释放，促进氧化应激和钙应激，导致胸腺细胞DNA损伤和细胞周期阻滞，引起细胞凋亡[6]。

2.2.2 T细胞发育信号变化

细菌分泌的特有组分-精氨酸脱氨酶(arginine deiminase, AD)减少血液中的L-精氨酸从而导致T细胞发育关键信号通路mTOR失调，诱导免疫抑制，加剧胸腺萎缩[36]。LPS诱导小鼠脓毒血症试验中，骨髓前体细胞表达的CCL19、CCL21和CCL25受体mRNA含量降低，导致淋巴样祖细胞向中枢免疫器官的归巢能力受损，胸腺抗感染功能受限[17]。过表达趋化因子配体2 (chemokine ligand, CCL2)的转基因小鼠的胸腺阴性选择能力紊乱，因此自身反应性T细胞缺失[39]。

2.3 其他因素

有研究表明白血病抑制因子(leukemia inhibitory factor, LIF)是E. coli来源的LPS诱导的急性胸腺萎缩的关键体内介质，但其如何介导胸腺变化还需进一步探讨[40]。将感染期间S. Typhimurium和LPS引起的基因变化进行对比，发现两者表达结果一样，但LPS引起基因表达的变化时间更早[6]。近年来肠道免疫得到关注，细菌感染机体后，其肠道菌群也会发生改变[41-42]。而肠道微生物抗原可从肠道运输至胸腺，诱导微生物特异性T细胞的增殖，进入外周后可抵抗相关病原体的侵害[43]。肠道微生物可影响免疫调节因子早幼粒细胞白血病锌指蛋白(promyelocytic leukemia zinc finger, PLZF)的稳态，并增加对结肠炎的易感性[44]。在鸡白痢沙门氏菌感染动物模型中，补充调节肠道菌群的混合益生菌后大肠杆菌和沙门氏菌的数量减少，胸腺指数提高，有效降低死亡率[45]。此外，树突状细胞作为组成胸腺微环境的重要组成成分，在细菌感染后第一时间呈递抗原，而当短时间大量细菌感染后则可能会导致早期呈递能力不足从而发生胸腺微环境紊乱，促进病原体逃避[46]。

3 细菌感染相关胸腺变化的应对策略 3.1 减少胸腺炎症

针对炎症引起的胸腺变化，体内使用小分子抑制剂SP600125可抑制JNK信号从而降低胞内炎症因子、活性氧(reactive oxygen species, ROS)，促凋亡基因Bax和caspase-3活性，降低线粒体膜电位，调节胸腺微环境，使胸腺凋亡量减少，然而胸腺细菌负荷量不受影响，这也从侧面反映了胸腺萎缩后的恢复中细菌负荷减少只是其中原因之一[11]。使用抗TNF-α抗体可完全保护E. coli引起的胸腺损伤，但仅部分逆转K. pneumoniae引起的胸腺萎缩[21]。同时使用抗生素来治疗S. Typhimurium感染小鼠后也恢复了正常的胸腺结构和胸腺细胞亚群的比例[8]。

3.2 降低胸腺激素水平

面对激素引起的胸腺萎缩，使用GC受体拮抗剂可部分恢复M. avium感染诱导的胸腺萎缩[28]。GC受体拮抗剂同时也对感染S. Typhimurium后的胸腺变化有一定的保护作用，其中DN2细胞群数量完全恢复，但胸腺整体恢复情况并无剂量依赖性[9]。针对LPS引起的胸腺萎缩，通过活性氧淬灭剂n-乙酰半胱氨酸(N-acetylcysteine, NAC)减少小鼠体内的皮质醇含量，可大大提高胸腺细胞的存活率，尤其是DN、DP和ISP细胞亚群，但并未减少细菌负荷[7]。

3.3 提升胸腺免疫功能

用针对LcrV LEEL32-35和DEEI203-206结合位点的单克隆抗体处理细胞，可以完全阻断胸腺细胞程序性死亡[20]。合成硒-有机化合物2,6-二吡啶-9-硒双环[3.3.1]壬基二溴化物进一步提升胸腺细胞的增殖活性，加强对Y. pestis的免疫反应[47]。含有CpG基序的合成寡脱氧核苷酸(CpG-ODNs)免疫佐剂使E. coli感染后的雏鸡胸腺DP细胞增殖，从而增强胸腺输出[14]。通过用一种小分子药物吡氰菊酯-β (pifithrin-β, PFT-β)短暂抑制p53基因联合角质形成细胞生长因子(keratinocyte growth factor, KGF)可促进骨髓移植后TECs细胞发育，从而增强胸腺细胞输出抗L. monocytogenes感染[48]。另有研究发现给瘦素缺失小鼠注射内毒素后，再给予瘦素进行处理可选择性刺激胸腺，有助于受损胸腺的重建和T细胞再生[16]。课题组前期研究通过胸腺内注射重组蛋白FOXN1可以有效促进BMT后TECs增殖及T细胞再生[49]。小分子抑制剂IM-12处理衰老小鼠后也有效促进胸腺重建以及T细胞再生[50]，这提示可通过技术手段恢复和提高胸腺功能。中药单体刺五加多糖可以促进环磷酰胺诱导的免疫抑制小鼠的脾细胞增殖以及增强抗菌作用[51]也说明了增强胸腺免疫功能后可发挥有效的抗病原体作用。

3.4 其他方法

抗LIF抗体预处理小鼠可明显减轻LPS所致胸腺萎缩[52]。LPS刺激后动物血清中TNF-α水平增加的同时瘦素浓度降低[53]。而瘦素可通过下调cPLA2和p38MAPK信号通路调节炎症和免疫反应从而减少LPS诱导的胸腺细胞凋亡量[54]。提示由LPS引起的胸腺萎缩也可通过瘦素来进行预防和治疗。

4 结论与展望

细菌感染使全球疾病负担高居不下，传统意义上，胸腺由于其“血液-胸腺屏障”受到一定的保护，但细菌感染后，胸腺也会发生一定程度的变化，相关机制也得到了较为深入的研究。对于细菌感染引起的胸腺变化，也发展了许多应对策略，并且取得一些较积极的效果。

本文总结了不同细菌感染导致的胸腺变化的效应，并讨论了潜在的分子致病机制，初步阐述可能存在的治疗或干预措施来减轻细菌感染引起的胸腺萎缩并恢复胸腺结构，这为治疗细菌感染导致的胸腺功能障碍方面的临床疾病提供了一定参考，也为细菌感染性疾病的预防和治疗提供了新的视角。

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细菌感染与胸腺结构和功能变化的研究进展
陈喆 , 田振振 , 宋银宏