沙门菌质粒毒力基因spv对DCs自噬、凋亡和免疫调节功能的影响
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摘要
目的:通过细胞模型和实验动物模型,研究沙门菌毒力基因(Salmonella plasmid virulence genes,spv)对树突状细胞(dendritic cells,DCs)自噬、凋亡和免疫调节功能的影响及其分子机制,探索通过调控细胞自噬和凋亡水平增强机体免疫功能以控制感染进程的新途径,并为后续新药靶位的发现提供理论和实验依据。
方法:
1.细胞模型的体外实验。以携带spv基因的伤寒沙门菌(Salmonella typhi,ST)ST8为研究对象,用含spv基因的鼠伤寒沙门菌标准毒株SR-11作为阳性对照、不携带spv基因的伤寒沙门菌ST10作为阴性对照,将细菌与小鼠骨髓来源的DCs(bone marrow-derived DCs,BMDCs)共培养;同时用不加细菌的正常细胞作对照组;另设自噬激动剂雷帕霉素(rapamycin,RAPA)干预组,即将细胞预先用含RAPA的培养基过夜处理后分别与上述三种细菌共培养。分别于不同时间段收获细胞,用Western blot法检测BMDCs自噬蛋白Beclin-1的表达,比色法测定其Caspase-3的活性,流式细胞术(flow cytometry,FCM)分析BMDCs的凋亡率、吞噬能力以及表面共刺激分子CD40、CD80和CD86的表达,混合淋巴细胞反应(mixed lymphocyte reaction,MLR)检测BMDCs刺激CD4+和CD8+初始型T(naive T)细胞增殖的能力,ELISA法测定培养液上清中IL-12、IFN-γ、IL-10和IL-4等细胞因子的水平,台盼蓝染色法进行活细胞计数,平板菌落计数法检测BMDCs内活菌数。
2.小鼠模型的体内实验。由于伤寒沙门菌是一种严格只对人类致病的病原体,没有合适的动物模型和有效的遗传学工具,本实验利用与其有非常近缘关系的鼠伤寒沙门菌建立动物感染模型,用鼠伤寒沙门菌标准毒株SR-11和不携带spv基因的低毒株BRD509经腹腔注射感染小鼠;同时以未感染细菌的小鼠作为正常对照组;另设RAPA干预组,即在感染模型建立后每天经腹腔注射适量RAPA。分别在不同时间段观察小鼠一般状态,处死小鼠后比较肝脏和脾脏的病理变化,免疫组化法检测肝脏和脾脏Beclin-1和Caspase-3蛋白的表达,FCM分析脾脏DCs的凋亡率、吞噬能力及表面共刺激分子CD40、CD80和CD86的表达,MLR检测脾脏DCs刺激naive T细胞增殖的能力,ELISA法测定血清中IL-12、IFN-γ、IL-10和IL-4等细胞因子的水平,平板菌落计数法检测小鼠肝脏和脾脏的活菌数。
结果:
1.用RAPA干预前,细菌与BMDCs共作用后2 h,ST10组的Beclin-1表达量高于SR-11组和ST8组,RAPA干预后0 h即可出现此差异;体内实验显示细菌感染早期,BRD509组小鼠脏器的Beclin-1表达高于SR-11组。用RAPA干预后体内外各组Beclin-1的表达均升高。
2.用RAPA干预前,体内外各组DCs的凋亡率和Caspase-3活性均随感染时间的延长逐渐升高。体外实验SR-11组和ST8组高于ST10组,用RAPA干预后,SR-11组和ST8组下降,而ST10组上升;体内小鼠脾脏DCs的凋亡率和Caspase-3活性表现为SR-11组高于BRD509组,用药后SR-11组降低,而BRD509组升高。
3.用RAPA干预前,随感染时间的延长,体内外实验各组DCs的吞噬能力均不断下降。体外实验ST10组的吞噬率低于SR-11组和ST8组;体内实验BRD509组的吞噬率低于SR-11组。用RAPA干预后,体内外各组DCs的吞噬率均明显下降。
4.用RAPA干预前,体内外各组DCs表面共刺激分子CD40、CD80和CD86的表达均随感染时间的延长逐渐升高,刺激naive T细胞增殖的能力也不断增强。体外实验显示ST10组明显强于SR-11组和ST8组;体内实验BRD509组明显强于SR-11组。用RAPA干预后,体内外各组DCs共刺激分子的表达均上升,naive T细胞的增殖程度亦升高。
5.用RAPA干预前,体内外各组IL-12和IFN-γ水平随着时间延长显著升高。体外表现为ST10组明显高于SR-11组和ST8组;体内实验BRD509组明显高于SR-11组。用RAPA干预后,体内外各组IL-12和IFN-γ的水平均上升。
6.用RAPA干预前,体内外各组在细菌感染早期均未检测到IL-10。体外感染后期SR-11组和ST8组BMDCs分泌的IL-10大量增加,明显高于ST10组;体内感染后期SR-11组的IL-10有表达,而BRD509则仍检测不到。用RAPA干预后,体内外各组IL-10的表达水平均低于用药前。不管RAPA干预与否,各组均未检测到IL-4的表达。
7.用RAPA干预前,体外实验SR-11组和ST8组BMDCs的存活率低于ST10组,而胞内活菌数则SR-11组和ST8组高于ST10;体内感染后期,SR-11组小鼠的一般状态较BRD509组差,脏器病理变化严重,活菌数亦较高。用RAPA干预后,体外实验SR-11组和ST8组BMDCs的存活率升高,而ST10组降低,胞内活菌数表现为SR-11组和ST8组降低,而ST10组升高;体内实验SR-11组脏器内活菌数降低而BRD509组升高,SR-11组脏器较用药前损伤减轻而BRD509组加重。
结论:
1.携带spv基因的沙门菌由于毒力较强,可通过抑制自噬,促进凋亡而加重感染,用RAPA干预其体内外感染模型后自噬被适度激活可对细胞和机体起到一定的保护作用;而无spv基因的沙门菌可通过适度激活自噬以减少细菌对细胞和机体的损害,对自身起到保护作用,当自噬被RAPA过度增强后,反而导致宿主的损伤。
2.携带spv基因的沙门菌能抑制小鼠DCs的成熟,使之刺激naive T细胞增殖的能力下降;RAPA可促进DCs的成熟,增强其抗原提呈能力。
3.沙门菌感染后刺激小鼠DCs诱导产生以Th1优势应答为主的免疫反应,机体产生的适度免疫应答能有效地清除低毒株的感染,而携带spv基因的沙门菌毒力株能抵抗和逃逸宿主的免疫防御。RAPA可通过增强自噬促进Th1类细胞因子的分泌并抑制Th2类免疫应答从而发挥抗胞内菌感染的作用。
Objective: To study the influence of Salmonella plasmid virulence genes (spv) on autophagy, apoptosis and immune function of dendritic cells (DCs), and explore the molecular mechanisms by cell and animal model, respectively. Then search for a new strategy for the control of infection process by regulating autophagy and apoptosis levels to enhance the immune function, and provide theoretical and experimental basis for discovering new drug target sites.
Methods:
1. The in vitro experiment using a cell model. Salmonella typhi ST8 carrying spv gene is the object of this study. Salmonella typhimurium strain SR-11 containing spv gene was used as a positive control, and Salmonella typhi ST10 as a negative one. Then the 3 strains of Salmonella were co-cultured with mouse bone marrow derived DCs (BMDCs). Another group of BMDCs were treated with an autophagy agonist rapamycin (RAPA) overnight before co-cultured with bacteria, and the uninfected BMDCs were used as normal control group. BMDCs in each group were harvested at different time points, and the autophagy protein Beclin-1 was detected by Western blot; Caspase-3 activity was assayed by colorimetry; the apoptosis rate, endocytosis rate and the expression of co-stimulatory molecules CD40, CD80 and CD86 were determined by flow cytometry (FCM); the proliferation of CD4+ and CD8+ naive T cells stimulated with BMDCs were detected by mixed lymphocyte reaction (MLR); IL-12, IFN-γ, IL-10 and IL-4 secretions were assayed by ELISA; the survival rate of BMDCs was determined by trypan blue stain and the viable bacterial quantities inside BMDCs were detected by plate count method.
2. The in vivo experiment using a mouse model. Salmonella typhi only strictly infects human beings and has no animal model. Salmonella typhimurium, a close relative to Salmonella tyhpi, was employed to setup the mouse infection model. Standard Salmonella typhimurium virulence strain SR-11 carrying spv gene were used in the intraperitoneal injection of mouse, and the attenuated strain BRD509 without spv gene was a negative control. Another group of mice were injected with RAPA after bacterial infection and the uninfected mice were used as normal control group. At different time points, the common condition of mouse was obsereved, then the pathological change of livers and spleens were compared after sacrifice of mice; Beclin-1 and Caspase-3 expression in livers and spleens were detected by immunohistochemisty; the apoptosis rate, endocytosis rate and CD40, CD80 and CD86 expression of splenic DCs were determined by FCM; the proliferation of naive T cells stimulated with splenic DCs were detected by MLR; IL-12, IFN-γ, IL-10 and IL-4 secretions in serum were assayed by ELISA, and the viable bacterial amounts in livers and spleens were detected by plate count method.
Results:
1. Before RAPA intervention, Beclin-1 expression of ST10 group was higher than SR-11 and ST8 group at 2 h post co-culture, and this difference could be observed since 0 h for those Salmonella-infected BMDCs pretreated with RAPA. The in vivo results showed that at the early stage of infection, Beclin-1 expression in organs of BRD509 group was higher than that in SR-11 group. RAPA intervention increased Beclin-1 expression in all groups.
2. Before RAPA intervention, the apoptosis rate and Caspase-3 activity of each group increased gradually. The in vitro results showed that SR-11 and ST8 group were higher than ST10 group, and the in vivo results displayed that SR-11 group was higher than BRD509 group. After RAPA treatment, SR-11 and ST8 group were decreased, while ST10 and BRD509 group were increased.
3. Before RAPA intervention, the endocytosis activity of DCs in each group was declining with the infection time. ST10 group was lower than SR-11 and ST8 group; BRD509 group was lower than SR-11 group. After intervention with RAPA, BMDCs endocytosis rate of each group were all decreased significantly.
4. Before RAPA intervention, CD40, CD80 and CD86 expression on DCs surface and the proliferation of naive T cells stimulated with DCs in all groups were gradually increased; the capability of ST10 group was significantly stronger than SR-11 and ST8 groups; the in vivo BRD509 group was significantly higher than that of SR-11 group. After RAPA intervention, both indexes in each group were increased.
5. Before RAPA intervention, all groups’IL-12 and IFN-γlevels were significantly increased, and ST10 group was significantly higher than both SR-11 and ST8 group.The in vivo results showed that BRD509 group was significantly higher than SR -11 group. After RAPA intervention, IL-12 and IFN-γof each group was increased.
6. Before RAPA intervention, IL-10 in each group could not detected during the early stage of infection. In the advanced infection stage, IL-10 secretion of BMDCs in SR-11 and ST8 group was detected significantly higher than ST10 group, and IL-10 of SR-11 group in vivo was detected, while BRD509 group still could not be detected. IL-10 expression of each group was decreased after intervented with RAPA. The expression of IL-4 was not detected in any group.
7. Before RAPA intervention, the BMDCs’survival rate of SR-11 and ST8 group were lower than ST10 group, but the numbers of intracellular viable bacteria in BMDCs of SR-11 and ST8 group were more than ST10 group. At the advanced stage of infection, mice of SR-11 group showed a worse common condition and more severe pathological changes in organs than BRD509 group, and the viable numbers of bacteria in organs was also higher. After RAPA intervention, the survival rate of BMDCs in SR-11 and ST8 group were increased, while ST10 group reduced, and the viable bacterial numbers in organs of SR-11 and ST8 group were decreased but ST10 group increased. The viable bacteria in organs of SR-11 group were decreased while BRD509 group increased, and the organ injury of SR-11 group was reduced but BRD509 group became more serious.
Conclusions:
1. Salmonella strains carrying spv gene can promote apoptosis to aggravate the infection by inhibit autophagy. RAPA intervention can protect cells and body by moderate activation of autophagy. Salmonella strains without spv gene can activate autophagy to reduce the bacterial damage to cells and body to protect bacteria themselves. RAPA intervention can lead to host injury when autophagy was hyper-enhanced.
2. Salmonella strains carrying spv gene can inhibit DCs maturation to decrease the proliferation of naive T cells. RAPA can promote DCs maturation and enhance the capability of antigen presentation.
3. Salmonella infection can stimulate murine DCs to induce a Th1 type immune response. Appropriate immune response can eradicate the infection of attenuated strains. However, spv containing Salmonella strains can resist and escape from immune defense. RAPA can promote the secretion of Th1 type cytokines and suppress Th2 type immune response by enhancing autophagy to strengthen the resistance to Salmonella infection.
方法:
1.细胞模型的体外实验。以携带spv基因的伤寒沙门菌(Salmonella typhi,ST)ST8为研究对象,用含spv基因的鼠伤寒沙门菌标准毒株SR-11作为阳性对照、不携带spv基因的伤寒沙门菌ST10作为阴性对照,将细菌与小鼠骨髓来源的DCs(bone marrow-derived DCs,BMDCs)共培养;同时用不加细菌的正常细胞作对照组;另设自噬激动剂雷帕霉素(rapamycin,RAPA)干预组,即将细胞预先用含RAPA的培养基过夜处理后分别与上述三种细菌共培养。分别于不同时间段收获细胞,用Western blot法检测BMDCs自噬蛋白Beclin-1的表达,比色法测定其Caspase-3的活性,流式细胞术(flow cytometry,FCM)分析BMDCs的凋亡率、吞噬能力以及表面共刺激分子CD40、CD80和CD86的表达,混合淋巴细胞反应(mixed lymphocyte reaction,MLR)检测BMDCs刺激CD4+和CD8+初始型T(naive T)细胞增殖的能力,ELISA法测定培养液上清中IL-12、IFN-γ、IL-10和IL-4等细胞因子的水平,台盼蓝染色法进行活细胞计数,平板菌落计数法检测BMDCs内活菌数。
2.小鼠模型的体内实验。由于伤寒沙门菌是一种严格只对人类致病的病原体,没有合适的动物模型和有效的遗传学工具,本实验利用与其有非常近缘关系的鼠伤寒沙门菌建立动物感染模型,用鼠伤寒沙门菌标准毒株SR-11和不携带spv基因的低毒株BRD509经腹腔注射感染小鼠;同时以未感染细菌的小鼠作为正常对照组;另设RAPA干预组,即在感染模型建立后每天经腹腔注射适量RAPA。分别在不同时间段观察小鼠一般状态,处死小鼠后比较肝脏和脾脏的病理变化,免疫组化法检测肝脏和脾脏Beclin-1和Caspase-3蛋白的表达,FCM分析脾脏DCs的凋亡率、吞噬能力及表面共刺激分子CD40、CD80和CD86的表达,MLR检测脾脏DCs刺激naive T细胞增殖的能力,ELISA法测定血清中IL-12、IFN-γ、IL-10和IL-4等细胞因子的水平,平板菌落计数法检测小鼠肝脏和脾脏的活菌数。
结果:
1.用RAPA干预前,细菌与BMDCs共作用后2 h,ST10组的Beclin-1表达量高于SR-11组和ST8组,RAPA干预后0 h即可出现此差异;体内实验显示细菌感染早期,BRD509组小鼠脏器的Beclin-1表达高于SR-11组。用RAPA干预后体内外各组Beclin-1的表达均升高。
2.用RAPA干预前,体内外各组DCs的凋亡率和Caspase-3活性均随感染时间的延长逐渐升高。体外实验SR-11组和ST8组高于ST10组,用RAPA干预后,SR-11组和ST8组下降,而ST10组上升;体内小鼠脾脏DCs的凋亡率和Caspase-3活性表现为SR-11组高于BRD509组,用药后SR-11组降低,而BRD509组升高。
3.用RAPA干预前,随感染时间的延长,体内外实验各组DCs的吞噬能力均不断下降。体外实验ST10组的吞噬率低于SR-11组和ST8组;体内实验BRD509组的吞噬率低于SR-11组。用RAPA干预后,体内外各组DCs的吞噬率均明显下降。
4.用RAPA干预前,体内外各组DCs表面共刺激分子CD40、CD80和CD86的表达均随感染时间的延长逐渐升高,刺激naive T细胞增殖的能力也不断增强。体外实验显示ST10组明显强于SR-11组和ST8组;体内实验BRD509组明显强于SR-11组。用RAPA干预后,体内外各组DCs共刺激分子的表达均上升,naive T细胞的增殖程度亦升高。
5.用RAPA干预前,体内外各组IL-12和IFN-γ水平随着时间延长显著升高。体外表现为ST10组明显高于SR-11组和ST8组;体内实验BRD509组明显高于SR-11组。用RAPA干预后,体内外各组IL-12和IFN-γ的水平均上升。
6.用RAPA干预前,体内外各组在细菌感染早期均未检测到IL-10。体外感染后期SR-11组和ST8组BMDCs分泌的IL-10大量增加,明显高于ST10组;体内感染后期SR-11组的IL-10有表达,而BRD509则仍检测不到。用RAPA干预后,体内外各组IL-10的表达水平均低于用药前。不管RAPA干预与否,各组均未检测到IL-4的表达。
7.用RAPA干预前,体外实验SR-11组和ST8组BMDCs的存活率低于ST10组,而胞内活菌数则SR-11组和ST8组高于ST10;体内感染后期,SR-11组小鼠的一般状态较BRD509组差,脏器病理变化严重,活菌数亦较高。用RAPA干预后,体外实验SR-11组和ST8组BMDCs的存活率升高,而ST10组降低,胞内活菌数表现为SR-11组和ST8组降低,而ST10组升高;体内实验SR-11组脏器内活菌数降低而BRD509组升高,SR-11组脏器较用药前损伤减轻而BRD509组加重。
结论:
1.携带spv基因的沙门菌由于毒力较强,可通过抑制自噬,促进凋亡而加重感染,用RAPA干预其体内外感染模型后自噬被适度激活可对细胞和机体起到一定的保护作用;而无spv基因的沙门菌可通过适度激活自噬以减少细菌对细胞和机体的损害,对自身起到保护作用,当自噬被RAPA过度增强后,反而导致宿主的损伤。
2.携带spv基因的沙门菌能抑制小鼠DCs的成熟,使之刺激naive T细胞增殖的能力下降;RAPA可促进DCs的成熟,增强其抗原提呈能力。
3.沙门菌感染后刺激小鼠DCs诱导产生以Th1优势应答为主的免疫反应,机体产生的适度免疫应答能有效地清除低毒株的感染,而携带spv基因的沙门菌毒力株能抵抗和逃逸宿主的免疫防御。RAPA可通过增强自噬促进Th1类细胞因子的分泌并抑制Th2类免疫应答从而发挥抗胞内菌感染的作用。
Objective: To study the influence of Salmonella plasmid virulence genes (spv) on autophagy, apoptosis and immune function of dendritic cells (DCs), and explore the molecular mechanisms by cell and animal model, respectively. Then search for a new strategy for the control of infection process by regulating autophagy and apoptosis levels to enhance the immune function, and provide theoretical and experimental basis for discovering new drug target sites.
Methods:
1. The in vitro experiment using a cell model. Salmonella typhi ST8 carrying spv gene is the object of this study. Salmonella typhimurium strain SR-11 containing spv gene was used as a positive control, and Salmonella typhi ST10 as a negative one. Then the 3 strains of Salmonella were co-cultured with mouse bone marrow derived DCs (BMDCs). Another group of BMDCs were treated with an autophagy agonist rapamycin (RAPA) overnight before co-cultured with bacteria, and the uninfected BMDCs were used as normal control group. BMDCs in each group were harvested at different time points, and the autophagy protein Beclin-1 was detected by Western blot; Caspase-3 activity was assayed by colorimetry; the apoptosis rate, endocytosis rate and the expression of co-stimulatory molecules CD40, CD80 and CD86 were determined by flow cytometry (FCM); the proliferation of CD4+ and CD8+ naive T cells stimulated with BMDCs were detected by mixed lymphocyte reaction (MLR); IL-12, IFN-γ, IL-10 and IL-4 secretions were assayed by ELISA; the survival rate of BMDCs was determined by trypan blue stain and the viable bacterial quantities inside BMDCs were detected by plate count method.
2. The in vivo experiment using a mouse model. Salmonella typhi only strictly infects human beings and has no animal model. Salmonella typhimurium, a close relative to Salmonella tyhpi, was employed to setup the mouse infection model. Standard Salmonella typhimurium virulence strain SR-11 carrying spv gene were used in the intraperitoneal injection of mouse, and the attenuated strain BRD509 without spv gene was a negative control. Another group of mice were injected with RAPA after bacterial infection and the uninfected mice were used as normal control group. At different time points, the common condition of mouse was obsereved, then the pathological change of livers and spleens were compared after sacrifice of mice; Beclin-1 and Caspase-3 expression in livers and spleens were detected by immunohistochemisty; the apoptosis rate, endocytosis rate and CD40, CD80 and CD86 expression of splenic DCs were determined by FCM; the proliferation of naive T cells stimulated with splenic DCs were detected by MLR; IL-12, IFN-γ, IL-10 and IL-4 secretions in serum were assayed by ELISA, and the viable bacterial amounts in livers and spleens were detected by plate count method.
Results:
1. Before RAPA intervention, Beclin-1 expression of ST10 group was higher than SR-11 and ST8 group at 2 h post co-culture, and this difference could be observed since 0 h for those Salmonella-infected BMDCs pretreated with RAPA. The in vivo results showed that at the early stage of infection, Beclin-1 expression in organs of BRD509 group was higher than that in SR-11 group. RAPA intervention increased Beclin-1 expression in all groups.
2. Before RAPA intervention, the apoptosis rate and Caspase-3 activity of each group increased gradually. The in vitro results showed that SR-11 and ST8 group were higher than ST10 group, and the in vivo results displayed that SR-11 group was higher than BRD509 group. After RAPA treatment, SR-11 and ST8 group were decreased, while ST10 and BRD509 group were increased.
3. Before RAPA intervention, the endocytosis activity of DCs in each group was declining with the infection time. ST10 group was lower than SR-11 and ST8 group; BRD509 group was lower than SR-11 group. After intervention with RAPA, BMDCs endocytosis rate of each group were all decreased significantly.
4. Before RAPA intervention, CD40, CD80 and CD86 expression on DCs surface and the proliferation of naive T cells stimulated with DCs in all groups were gradually increased; the capability of ST10 group was significantly stronger than SR-11 and ST8 groups; the in vivo BRD509 group was significantly higher than that of SR-11 group. After RAPA intervention, both indexes in each group were increased.
5. Before RAPA intervention, all groups’IL-12 and IFN-γlevels were significantly increased, and ST10 group was significantly higher than both SR-11 and ST8 group.The in vivo results showed that BRD509 group was significantly higher than SR -11 group. After RAPA intervention, IL-12 and IFN-γof each group was increased.
6. Before RAPA intervention, IL-10 in each group could not detected during the early stage of infection. In the advanced infection stage, IL-10 secretion of BMDCs in SR-11 and ST8 group was detected significantly higher than ST10 group, and IL-10 of SR-11 group in vivo was detected, while BRD509 group still could not be detected. IL-10 expression of each group was decreased after intervented with RAPA. The expression of IL-4 was not detected in any group.
7. Before RAPA intervention, the BMDCs’survival rate of SR-11 and ST8 group were lower than ST10 group, but the numbers of intracellular viable bacteria in BMDCs of SR-11 and ST8 group were more than ST10 group. At the advanced stage of infection, mice of SR-11 group showed a worse common condition and more severe pathological changes in organs than BRD509 group, and the viable numbers of bacteria in organs was also higher. After RAPA intervention, the survival rate of BMDCs in SR-11 and ST8 group were increased, while ST10 group reduced, and the viable bacterial numbers in organs of SR-11 and ST8 group were decreased but ST10 group increased. The viable bacteria in organs of SR-11 group were decreased while BRD509 group increased, and the organ injury of SR-11 group was reduced but BRD509 group became more serious.
Conclusions:
1. Salmonella strains carrying spv gene can promote apoptosis to aggravate the infection by inhibit autophagy. RAPA intervention can protect cells and body by moderate activation of autophagy. Salmonella strains without spv gene can activate autophagy to reduce the bacterial damage to cells and body to protect bacteria themselves. RAPA intervention can lead to host injury when autophagy was hyper-enhanced.
2. Salmonella strains carrying spv gene can inhibit DCs maturation to decrease the proliferation of naive T cells. RAPA can promote DCs maturation and enhance the capability of antigen presentation.
3. Salmonella infection can stimulate murine DCs to induce a Th1 type immune response. Appropriate immune response can eradicate the infection of attenuated strains. However, spv containing Salmonella strains can resist and escape from immune defense. RAPA can promote the secretion of Th1 type cytokines and suppress Th2 type immune response by enhancing autophagy to strengthen the resistance to Salmonella infection.
引文
[1] Siddiqui FJ, Rabbani F, Hasan R, et al. Typhoid fever in children: some epidemiological considerations from Karachi, Pakistan. Int J Infect Dis, 2006; 10(3): 215-222.
[2] Crump JA, Mintz ED. Global trends in typhoid and paratyphoid fever. Clin Infect Dis, 2010; 50(2): 241-246.
[3]肖黔林,周忠海,李秋丽.质粒分析、噬菌体定型及耐药谱测定在伤寒流行病学调查中的应用.中华流行病学杂志, 1987; 5(5): 272-275.
[4]黄瑞,穆荣普.伤寒沙门氏菌耐药性及其耐药质粒的监测.中华传染病杂志, 1994; 12(4): 204-206.
[5]黄瑞,吴淑燕,闻玉梅.伤寒沙门菌耐药质粒pRST98介导细菌毒力的研究.中华微生物学与免疫学杂志, 2001; 21(3): 302-305.
[6] Ygberg SE, Clements MO, Rytkonen A, et al. Polynucleotide phosphorylase negatively controls spv virulence gene expression in Salmonella enterica. Infect Immun, 2006; 74(2): 1243-1254.
[7] Madajczak G, Binek M. Influence of spv plasmid genes group in Salmonella Enteritidis virulence for chickens I Occurrence of spv plasmid genes group in Salmonella Enteritidis large virulence plasmid. Med Dosw Mikrobiol, 2005; 57(2): 163-174.
[8]黄瑞,吴淑燕,张学光.伤寒杆菌耐药质粒pRST98毒力基因的研究.中华微生物学与免疫学杂志, 2003; 23(5): 393-396.
[9] Huang R, Wu S, Zhang X, et al. Molecular analysis and identification of virulence gene on pRST98 from multi-drug resistant Salmonella typhi. Cell Mol Immunol, 2005; 2(2): 136-140.
[10] Cella M, Engering A, Pinet V, et al. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature, 1997; 388(6644): 782-787.
[11] Pulendran B. Modulating vaccine responses with dendritic cells and toll-like receptors. Immunol Rev, 2004; 199(1): 227-250.
[12] Bell D, Young JW, Banchereau J. Dendritic cells. Adv Immunol, 1999; 72: 255-321.
[13] Lopez CB, Moltedo B, Alexopoulou L, et al. TLR-independent induction of dendritic cell maturation and adaptive immunity by negative-strand RNA viruses. J Immunol, 2004; 173(11): 6882-6889.
[14] Turley SJ, Steinman RM, Mellman I, et al. Propagation and culture of dendritic cells. Dendritic cells: biology and clinical applications. Academic Press, 1999: 544.
[15] Ardavin C, Martinez del Hoyo G, Martin P, et al. Origin and differentiation of dendritic cells. Trends Immunol, 2001; 22(12): 691-700.
[16] Bueno SM, Tobar JA, Iruretagoyena MI, et al. Molecular interactions between dendritic cells and Salmonella: escape from adaptive immunity and implications on pathogenesis. Crit Rev Immunol, 2005; 25(5): 389-403.
[17] Mary JW. Monocyte and dendritic cell recruitment and activation during oral Salmonella infection. Immunol Lett, 2007; 112(2): 68-74.
[18] Finlay BB, McFadden G. Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell, 2006; 124(4): 767-782.
[19] Tobar JA, Gonzalez PA, Kalergis AM. Salmonella escape from antigen presentation can be overcome by targeting bacteria to Fc gamma receptors on dendritic cells. J Immunol, 2004; 173(6): 4058-4065.
[20] Bueno SM, Riedel CA, Carreno LJ, et al. Virulence mechanisms displayed by Salmonella to impair dendritic cell function. Curr Med Chem, 2010; 17(22): 1156-1166.
[21] Cheminay C, Mohlenbrink A, Hensel M. Intracellular Salmonella inhibit antigen presentation by dendritic cells. J Immunol, 2005; 174(5): 2892-2899.
[22] Tobar JA, Carreno LJ, Bueno SM, et al. Virulent Salmonella enterica serovar typhimurium evades adaptive immunity by preventing dendritic cells from activating T cells. Infect Immun, 2006; 74(11): 6438-6448.
[23] Levine B, Deretic V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol, 2007; 7(10): 767-777.
[24] Mizushima N, Ohsumi Y, Yoshimori T. Autophagysome formation in mammalian cells. Cell Struct Funct, 2002; 27(6): 421-429.
[25] Lum JJ, Bauer DE, Kong M, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell, 2005; 120(2): 237-248.
[26] Yi X, Chinnaswamy J, Liu XD, et al. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity, 2007; 27(1): 135-144.
[27] Birmingham CL, Higgins DE, Brumell JH. Avoiding death by autophagy: interactions of Listeria monocytogenes with the macrophage autophagy system. Autophagy, 2008; 4(3): 368-371.
[28] Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest, 2005; 115(10): 2679-2688.
[29] Yrlid U, and Mary JW. Salmonella-induced apoptosis of infected macrophages results in presentation of a bacteria-encoded antigen after uptake by bystander dendritic cells. J Exp Med, 2000; 191(4): 613-624.
[30] Weeks S, Hill J, Friedlander A, et al. Anti-V antigen antibody protects macrophages from Yersinia pestis-induced cell death and promotes phagocytosis. Microb Pathog, 2002; 32(5): 227.
[31] Yousefi S, Perozzo R, Schmid I, et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol, 2006; 8(10): 1124-1132.
[32] Lockshin RA, Zakeri Z. Caspase-independent cell deaths. Curr Opin Cell Biol, 2002; 14(6): 727-733.
[33] Edinger AL, Thompson CB. Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol, 2004; 16(6): 663-669.
[34] Pattingre S, Tassa A, Qu X, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell, 2005; 122(6): 927-939.
[35] Weichhart T, Saemann MD. The PI3K/Akt/mTOR pathway in innate immune cells: emerging therapeutic applications. Ann Rheum Dis, 2008; 67(S3): iii70-74.
[36]吴淑燕,李琼,储元元,等.自噬对鼠伤寒沙门菌所致的巨噬细胞凋亡的影响.微生物学通报, 2010 (已录用).
[37] Birmingham CL, Brumell JH. Methods to monitor autophagy of Salmonella enterica serovar typhimurium. Methods Enzymol, 2009; 452: 325-343.
[38] Holger H, Timucin T, Alison JL, et al. Rapamycin inhibits macropinocytosis and mannose receptor-mediated endocytosis by bone marrow-derived dendritic cells. Blood, 2002; 100(3): 1084-1087.
[39]周德庆.微生物学教程.北京:高等教育出版社, 1996: 185.
[40] Jagannath C, Lindsey DR, Dhandayuthapani S, et al. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med, 2009; 15(3): 267-276.
[41] Bueno SM, Gonzalez PA, Carreno LJ, et al. The capacity of Salmonella to survive inside dendritic cells and prevent antigen presentation to T cells is host specific. Immunology, 2008; 124(4): 522-533.
[42] Richter-Dahlfors A, Buchan AM, et al. Murine salmonellosis studied by confocal microscopy: Salmonella typhimurium resides intracellularly inside macrophages and exerts a cytotoxic effect on phagocytes in vivo. J Exp Med, 1997, 186(4): 569-580.
[43] Valdez Y, Ferreira RB, Finlay BB. Molecular mechanisms of Salmonella virulence and host resistance. Curr Top Microbiol Immunol, 2009; 337: 93-127.
[44] Monack DM, Mueller A, Falkow S. Persistent bacterial infections: the interface of the pathogen and the host immune system. Nat Rev Microbiol, 2004; 2(9): 747-765.
[45] Park MA, Yacoub A, Rahmani M, et al. OSU-03012 stimulates PKR-like endoplasmic reticulum-dependent increases in 70-kDa heat shock protein expression, attenuating its lethal actions in transformed cells. Mol Pharmacol, 2008; 73(4): 1168-1184.
[46] Finlay BB, Hancock RE. Can innate immunity be enhanced to treat microbial infections? Nat Rev Microbiol, 2004; 2(6): 497-504.
[47] Schwegmann A, Brombacher F. Host-directed drug targeting of factors hijacked by pathogens. Sci Signal, 2008; 1(29): re8.
[48] Madden DT, Egger L, Bredesen DE. A calpain-like protease inhibits autophagic cell death. Autophagy, 2007; 3(5): 519-522.
[49] Sun Q, Fan W, Zhong Q. Regulation of Beclin 1 in autophagy. Autophagy, 2009; 5(5): 713-716.
[50] Yue ZY, Jin SK, Yang CW, et al. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci, 2003; 100: 15077-15082.
[51] Grant AJ, Sheppard M, Deardon R, et al. Caspase-3-dependent phagocyte death during systemic Salmonella enterica serovar typhimurium infection of mice. Immunology, 2008; 125(1): 28-37.
[52] Svensson M, Cecilia J, Mary JW. Salmonella enterica serovar typhimurium induced maturation of bone marrow-derived dendritic cells. Infect Immun, 2000; 68(11): 6311-6320.
[53] Hathcock KS, Laszlo G, Pucillo C, et al. Comparative analysis of B7-1 and B7-2costimulatory ligands: expression and function. J Exp Med, 1994; 180(2): 631-640.
[54] Nauciel C, Espinasse-Maes F. Role ofγinterferon and tumor necrosis factorαin resistance to Salmonella typhimurium infection. Infect Immun, 1992; 60(2): 450-454.
[55] Gulig PA, Doyle TJ, Clare-Salzler MJ, et al. Systemic infection of mice by wild-type but not Spv- Salmonella typhimurium is enhanced by neutralization ofγinterferon and tumor necrosis factorα. Infect Immun, 1997; 65(12): 5191-5197.
[56] Sullivan BA, Nagarajan NA, Kronenberg M. CD1 and MHC II find different means to the same end. Trends Immunol, 2005; 26(5): 282-288.
[57]龚非力,等.医学免疫学.高等教育出版社, 2009: 54-55, 252.
[58] Gulig PA, Doyle TJ. The Salmonella typhimurium virulence plasmid increases the growth rate of salmonellae in mice. Infect Immun, 1993; 61(2): 504-511.
[1] Steinman RM. Dendritic cells in vivo: a key target for a new vaccine science. Immunity, 2008; 29(3): 319-324.
[2] Kawai T and Akira S. TLR signaling. Semin Immunol, 2007; 19(1): 24-32.
[3] Trinchieri G, Sher A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol, 2007; 7 (3): 179-190.
[4] Akiras, Takeda K. Toll-like receptor signalling. Nat Rev Immunol, 2004; 4(7): 499-511.
[5] Goldstein DR, Tesar BM, Akira S, et al. Critical role of the toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J Clin Invest, 2003; 111(10): 1571-1578.
[6] Nakamura K, Miyazato A, Koguchi Y, et al. Toll-like receptor 2 (TLR2) and dectin-1 contribute to the production of IL-12p40 by bone marrow-derived dendritic cells infected with Penicillium marneffei. Microbes Infect, 2008; 10(10-11): 1223-1227.
[7] Vanhoutte F, Breuilh L, Fontaine J, et al. Toll-like receptor (TLR)2 and TLR3 sensing is required for dendritic cell activation, but dispensable to control Schistosoma mansoni infection and pathology. Microbes Infect, 2007; 9(14-15): 1606-1613.
[8] Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol, 2004; 5(10): 987-995.
[9] Hoshino K, Kaisho T. Nucleic acid sensing toll-like receptors in dendritic cells. Curr Opin Immunol, 2008; 20(4): 408-413.
[10] Means TK, Hayashi F, Smith KD, et al. The toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells. J Immunol, 2003; 170(10): 5165-5175.
[11] Seya T, Akazawa T, Tsujita T, et al. Role of toll-like receptors inadjuvant-augmented immune therapy. Evid-based Compl Alt, 2006; 3(1): 31-38.
[12] Manicassamy S, PulendranB. Modulation of adaptive immunity with toll-like receptors. Semin Immunol, 2009; 21(4): 185-193.
[13] Shortman K, Liu Y. Mouse and human dendritic cell subtypes. Nat Rev Immunol, 2002; 2(3): 151-161.
[14] Golden JM, LaCasse CJ, Simova DV, et al. Differential mediator production by dendritic cells upon toll-like receptor stimulation does not impact T cell cytokine expression. Immunol Lett, 2008; 118(1): 30-35.
[15] Chen Z, Cheng Y, Xu Y, et al. Expression profiles and function of toll-like receptors 2 and 4 in peripheral blood mononuclear cells of chronic hepatitis B patients. Clin Immunol, 2008; 128(3): 400-408.
[16] Lester RT, Yao XD, Ball TB, et al. Toll-like receptor expression and responsiveness are increased in viraemic HIV-1 infection. Aids, 2008; 22(6): 685-694.
[17] de Kruif MD, Setiati TE, Mairuhu AT, et al. Differential gene expression changes in children with severe dengue virus infections. PloS Negl Trop Dis, 2008; 2(4): e215.
[18] Ketloy C, Engering A, Srichairatanakul U, et al. Expression and function of toll-like receptors on dendritic cells and other antigen presenting cells from non-human primates. Vet Immunol Immunopathol, 2008; 125(1-2): 18-30.
[19] Edwards AD, Diebold SS, Slack EM, et al. Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α+ DC correlates with unresponsiveness to imidazoquinolines. Eur J Immunol, 2003; 33(4): 827-833.
[20] Maldonado-Lopez R, De Smedt T, Pajak B, et al. Role of CD8α+ and CD8α? dendritic cells in the induction of primary immune responses in vivo. J Leukoc Biol, 1999; 66(2): 242-246.
[21] Manickasingham SP, Edwards AD, Schulz O, et al. The ability of murine dendritic cell subsets to direct Th differentiation is dependent on microbial signals. Eur J Immunol, 2003; 33(1): 101-107.
[22] Blander JM. Coupling Toll-like receptor signaling with phagocytosis: potentiation of antigen presentation. Trends Immunol, 2007; 28(1): 19-25.
[23] Blander J M, Medzhitov R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature, 2006; 440(7085): 808-812.
[24] Delamarre L, Holcombe H, Meilman I. Presentation of exogenous antigens on Major Histocompatibility Complex (MHC) class I and MHC class II molecules isdifferentially regulated during dendritic cell maturation. J Exp Med, 2003; 198(1): 111-122.
[25] Datta SK, Redecke V, Prilliman KR, et al. A subset of toll-like receptor ligands induces cross-presentation by bone marrow-derived dendritic cells. J Immunol, 2003; 170(8): 4102-4110.
[26] Boele LC, Bajramovic JJ, de-Vries AM, et al. Activation of toll-like receptors and dendritic cells by a broad range of bacterial molecules. Cell Immunol, 2009; 255(1-2): 17-25.
[27] Hoshino K, Kaisho T, Iwabe T, et al. Differential involvement of IFN-beta in toll-like receptor-stimulated dendritic cell activation. Int Immunol, 2002; 14(10): 1225-1231.
[28] Mattei F, Schiavoni G, Belardelli F, et al. IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J Immunol, 2001; 167(3): 1179-1187.
[29] Lebre MC, Antons JC, Kalinski P, et al. Double-stranded RNA-exposed human keratinocytes promote Th1 responses by inducing a type-1 polarized phenotype in dendritic cells: role of keratinocyte-derived tumor necrosis factor alpha, type I interferons, and interleukin-18. J Invest Dermatol, 2003; 120(6): 990-997.
[30] Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science, 2003; 299(5609): 1033-1036.
[31] Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol, 2002; 20: 709-760.
[32] Boullart AC, Aarntzen EH, Verdijk P, et al. Maturation of monocyte-derived dendritic cells with toll-like receptor 3 and 7/8 ligands combined with prostaglandin E2 results in high interleukin-12 production and cell migration. Cancer Immunol Immunother, 2008; 57(11): 1589-1597.
[33] Cao W, Liu YJ. Innate immune functions of plasmacytoid dendritic cells. Curr Opin Immunol, 2007; 19:(1) 24-30.
[34] Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell, 2008; 132(3): 344-362.
[35] Kawai T, Akira S. Signaling to NF-kappaB by toll-like receptors. Trends Mol Med, 2007; 13(11): 460-469.
[36] Kaisho T, Takeuchi O, Kawai T, et al. Endotoxin-induced maturation ofMyD88-deficient dendritic cells. J Immunol, 2001; 166(9): 5688-5694.
[37] Yamamoto M, Sato S, Hemmi H, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science, 2003; 301(5633): 640-643.
[38] Beutler B. Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases. Immunol Rev, 2009; 227(1): 248-263.
[39] Beutler BA. TLRs and innate immunity. Blood, 2009; 113(7): 1399-1407.
[40] Foster SL, Medzhitov R. Gene-specific control of the TLR-inducedinflammatory response. Clin Immunol, 2009; 130(1): 7-15.
[41] Fukao T, TanabeM, Terauchi Y, et al. PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nat Immunol, 2002; 3(9): 875-881.
[42] Dalpke A, Heeg K, Bartz H, et al. Regulation of innate immunity by suppressor of cytokine signaling (SOCS) proteins. Immunobiology, 2008; 213(304): 225-235.
[43] Mansell A, Smith R, Doyle SL, et al. Suppressor of cytokine signaling 1 negatively regulates toll-like receptor signaling by mediating Mal degradation. Nat Immunol, 2006; 7(2):148-155.
[44] Manicassamy S, Ravindran R, Deng J, et al. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat Med, 2009; 15(4): 401-409.
[45] Mbow ML, Sarisky M. Modulating toll-like receptor signalling as a novel antiinfective approach. Drug News Perspect, 2005; 18(3): 179-184.
[2] Crump JA, Mintz ED. Global trends in typhoid and paratyphoid fever. Clin Infect Dis, 2010; 50(2): 241-246.
[3]肖黔林,周忠海,李秋丽.质粒分析、噬菌体定型及耐药谱测定在伤寒流行病学调查中的应用.中华流行病学杂志, 1987; 5(5): 272-275.
[4]黄瑞,穆荣普.伤寒沙门氏菌耐药性及其耐药质粒的监测.中华传染病杂志, 1994; 12(4): 204-206.
[5]黄瑞,吴淑燕,闻玉梅.伤寒沙门菌耐药质粒pRST98介导细菌毒力的研究.中华微生物学与免疫学杂志, 2001; 21(3): 302-305.
[6] Ygberg SE, Clements MO, Rytkonen A, et al. Polynucleotide phosphorylase negatively controls spv virulence gene expression in Salmonella enterica. Infect Immun, 2006; 74(2): 1243-1254.
[7] Madajczak G, Binek M. Influence of spv plasmid genes group in Salmonella Enteritidis virulence for chickens I Occurrence of spv plasmid genes group in Salmonella Enteritidis large virulence plasmid. Med Dosw Mikrobiol, 2005; 57(2): 163-174.
[8]黄瑞,吴淑燕,张学光.伤寒杆菌耐药质粒pRST98毒力基因的研究.中华微生物学与免疫学杂志, 2003; 23(5): 393-396.
[9] Huang R, Wu S, Zhang X, et al. Molecular analysis and identification of virulence gene on pRST98 from multi-drug resistant Salmonella typhi. Cell Mol Immunol, 2005; 2(2): 136-140.
[10] Cella M, Engering A, Pinet V, et al. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature, 1997; 388(6644): 782-787.
[11] Pulendran B. Modulating vaccine responses with dendritic cells and toll-like receptors. Immunol Rev, 2004; 199(1): 227-250.
[12] Bell D, Young JW, Banchereau J. Dendritic cells. Adv Immunol, 1999; 72: 255-321.
[13] Lopez CB, Moltedo B, Alexopoulou L, et al. TLR-independent induction of dendritic cell maturation and adaptive immunity by negative-strand RNA viruses. J Immunol, 2004; 173(11): 6882-6889.
[14] Turley SJ, Steinman RM, Mellman I, et al. Propagation and culture of dendritic cells. Dendritic cells: biology and clinical applications. Academic Press, 1999: 544.
[15] Ardavin C, Martinez del Hoyo G, Martin P, et al. Origin and differentiation of dendritic cells. Trends Immunol, 2001; 22(12): 691-700.
[16] Bueno SM, Tobar JA, Iruretagoyena MI, et al. Molecular interactions between dendritic cells and Salmonella: escape from adaptive immunity and implications on pathogenesis. Crit Rev Immunol, 2005; 25(5): 389-403.
[17] Mary JW. Monocyte and dendritic cell recruitment and activation during oral Salmonella infection. Immunol Lett, 2007; 112(2): 68-74.
[18] Finlay BB, McFadden G. Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell, 2006; 124(4): 767-782.
[19] Tobar JA, Gonzalez PA, Kalergis AM. Salmonella escape from antigen presentation can be overcome by targeting bacteria to Fc gamma receptors on dendritic cells. J Immunol, 2004; 173(6): 4058-4065.
[20] Bueno SM, Riedel CA, Carreno LJ, et al. Virulence mechanisms displayed by Salmonella to impair dendritic cell function. Curr Med Chem, 2010; 17(22): 1156-1166.
[21] Cheminay C, Mohlenbrink A, Hensel M. Intracellular Salmonella inhibit antigen presentation by dendritic cells. J Immunol, 2005; 174(5): 2892-2899.
[22] Tobar JA, Carreno LJ, Bueno SM, et al. Virulent Salmonella enterica serovar typhimurium evades adaptive immunity by preventing dendritic cells from activating T cells. Infect Immun, 2006; 74(11): 6438-6448.
[23] Levine B, Deretic V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol, 2007; 7(10): 767-777.
[24] Mizushima N, Ohsumi Y, Yoshimori T. Autophagysome formation in mammalian cells. Cell Struct Funct, 2002; 27(6): 421-429.
[25] Lum JJ, Bauer DE, Kong M, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell, 2005; 120(2): 237-248.
[26] Yi X, Chinnaswamy J, Liu XD, et al. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity, 2007; 27(1): 135-144.
[27] Birmingham CL, Higgins DE, Brumell JH. Avoiding death by autophagy: interactions of Listeria monocytogenes with the macrophage autophagy system. Autophagy, 2008; 4(3): 368-371.
[28] Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest, 2005; 115(10): 2679-2688.
[29] Yrlid U, and Mary JW. Salmonella-induced apoptosis of infected macrophages results in presentation of a bacteria-encoded antigen after uptake by bystander dendritic cells. J Exp Med, 2000; 191(4): 613-624.
[30] Weeks S, Hill J, Friedlander A, et al. Anti-V antigen antibody protects macrophages from Yersinia pestis-induced cell death and promotes phagocytosis. Microb Pathog, 2002; 32(5): 227.
[31] Yousefi S, Perozzo R, Schmid I, et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol, 2006; 8(10): 1124-1132.
[32] Lockshin RA, Zakeri Z. Caspase-independent cell deaths. Curr Opin Cell Biol, 2002; 14(6): 727-733.
[33] Edinger AL, Thompson CB. Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol, 2004; 16(6): 663-669.
[34] Pattingre S, Tassa A, Qu X, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell, 2005; 122(6): 927-939.
[35] Weichhart T, Saemann MD. The PI3K/Akt/mTOR pathway in innate immune cells: emerging therapeutic applications. Ann Rheum Dis, 2008; 67(S3): iii70-74.
[36]吴淑燕,李琼,储元元,等.自噬对鼠伤寒沙门菌所致的巨噬细胞凋亡的影响.微生物学通报, 2010 (已录用).
[37] Birmingham CL, Brumell JH. Methods to monitor autophagy of Salmonella enterica serovar typhimurium. Methods Enzymol, 2009; 452: 325-343.
[38] Holger H, Timucin T, Alison JL, et al. Rapamycin inhibits macropinocytosis and mannose receptor-mediated endocytosis by bone marrow-derived dendritic cells. Blood, 2002; 100(3): 1084-1087.
[39]周德庆.微生物学教程.北京:高等教育出版社, 1996: 185.
[40] Jagannath C, Lindsey DR, Dhandayuthapani S, et al. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med, 2009; 15(3): 267-276.
[41] Bueno SM, Gonzalez PA, Carreno LJ, et al. The capacity of Salmonella to survive inside dendritic cells and prevent antigen presentation to T cells is host specific. Immunology, 2008; 124(4): 522-533.
[42] Richter-Dahlfors A, Buchan AM, et al. Murine salmonellosis studied by confocal microscopy: Salmonella typhimurium resides intracellularly inside macrophages and exerts a cytotoxic effect on phagocytes in vivo. J Exp Med, 1997, 186(4): 569-580.
[43] Valdez Y, Ferreira RB, Finlay BB. Molecular mechanisms of Salmonella virulence and host resistance. Curr Top Microbiol Immunol, 2009; 337: 93-127.
[44] Monack DM, Mueller A, Falkow S. Persistent bacterial infections: the interface of the pathogen and the host immune system. Nat Rev Microbiol, 2004; 2(9): 747-765.
[45] Park MA, Yacoub A, Rahmani M, et al. OSU-03012 stimulates PKR-like endoplasmic reticulum-dependent increases in 70-kDa heat shock protein expression, attenuating its lethal actions in transformed cells. Mol Pharmacol, 2008; 73(4): 1168-1184.
[46] Finlay BB, Hancock RE. Can innate immunity be enhanced to treat microbial infections? Nat Rev Microbiol, 2004; 2(6): 497-504.
[47] Schwegmann A, Brombacher F. Host-directed drug targeting of factors hijacked by pathogens. Sci Signal, 2008; 1(29): re8.
[48] Madden DT, Egger L, Bredesen DE. A calpain-like protease inhibits autophagic cell death. Autophagy, 2007; 3(5): 519-522.
[49] Sun Q, Fan W, Zhong Q. Regulation of Beclin 1 in autophagy. Autophagy, 2009; 5(5): 713-716.
[50] Yue ZY, Jin SK, Yang CW, et al. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci, 2003; 100: 15077-15082.
[51] Grant AJ, Sheppard M, Deardon R, et al. Caspase-3-dependent phagocyte death during systemic Salmonella enterica serovar typhimurium infection of mice. Immunology, 2008; 125(1): 28-37.
[52] Svensson M, Cecilia J, Mary JW. Salmonella enterica serovar typhimurium induced maturation of bone marrow-derived dendritic cells. Infect Immun, 2000; 68(11): 6311-6320.
[53] Hathcock KS, Laszlo G, Pucillo C, et al. Comparative analysis of B7-1 and B7-2costimulatory ligands: expression and function. J Exp Med, 1994; 180(2): 631-640.
[54] Nauciel C, Espinasse-Maes F. Role ofγinterferon and tumor necrosis factorαin resistance to Salmonella typhimurium infection. Infect Immun, 1992; 60(2): 450-454.
[55] Gulig PA, Doyle TJ, Clare-Salzler MJ, et al. Systemic infection of mice by wild-type but not Spv- Salmonella typhimurium is enhanced by neutralization ofγinterferon and tumor necrosis factorα. Infect Immun, 1997; 65(12): 5191-5197.
[56] Sullivan BA, Nagarajan NA, Kronenberg M. CD1 and MHC II find different means to the same end. Trends Immunol, 2005; 26(5): 282-288.
[57]龚非力,等.医学免疫学.高等教育出版社, 2009: 54-55, 252.
[58] Gulig PA, Doyle TJ. The Salmonella typhimurium virulence plasmid increases the growth rate of salmonellae in mice. Infect Immun, 1993; 61(2): 504-511.
[1] Steinman RM. Dendritic cells in vivo: a key target for a new vaccine science. Immunity, 2008; 29(3): 319-324.
[2] Kawai T and Akira S. TLR signaling. Semin Immunol, 2007; 19(1): 24-32.
[3] Trinchieri G, Sher A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol, 2007; 7 (3): 179-190.
[4] Akiras, Takeda K. Toll-like receptor signalling. Nat Rev Immunol, 2004; 4(7): 499-511.
[5] Goldstein DR, Tesar BM, Akira S, et al. Critical role of the toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J Clin Invest, 2003; 111(10): 1571-1578.
[6] Nakamura K, Miyazato A, Koguchi Y, et al. Toll-like receptor 2 (TLR2) and dectin-1 contribute to the production of IL-12p40 by bone marrow-derived dendritic cells infected with Penicillium marneffei. Microbes Infect, 2008; 10(10-11): 1223-1227.
[7] Vanhoutte F, Breuilh L, Fontaine J, et al. Toll-like receptor (TLR)2 and TLR3 sensing is required for dendritic cell activation, but dispensable to control Schistosoma mansoni infection and pathology. Microbes Infect, 2007; 9(14-15): 1606-1613.
[8] Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol, 2004; 5(10): 987-995.
[9] Hoshino K, Kaisho T. Nucleic acid sensing toll-like receptors in dendritic cells. Curr Opin Immunol, 2008; 20(4): 408-413.
[10] Means TK, Hayashi F, Smith KD, et al. The toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells. J Immunol, 2003; 170(10): 5165-5175.
[11] Seya T, Akazawa T, Tsujita T, et al. Role of toll-like receptors inadjuvant-augmented immune therapy. Evid-based Compl Alt, 2006; 3(1): 31-38.
[12] Manicassamy S, PulendranB. Modulation of adaptive immunity with toll-like receptors. Semin Immunol, 2009; 21(4): 185-193.
[13] Shortman K, Liu Y. Mouse and human dendritic cell subtypes. Nat Rev Immunol, 2002; 2(3): 151-161.
[14] Golden JM, LaCasse CJ, Simova DV, et al. Differential mediator production by dendritic cells upon toll-like receptor stimulation does not impact T cell cytokine expression. Immunol Lett, 2008; 118(1): 30-35.
[15] Chen Z, Cheng Y, Xu Y, et al. Expression profiles and function of toll-like receptors 2 and 4 in peripheral blood mononuclear cells of chronic hepatitis B patients. Clin Immunol, 2008; 128(3): 400-408.
[16] Lester RT, Yao XD, Ball TB, et al. Toll-like receptor expression and responsiveness are increased in viraemic HIV-1 infection. Aids, 2008; 22(6): 685-694.
[17] de Kruif MD, Setiati TE, Mairuhu AT, et al. Differential gene expression changes in children with severe dengue virus infections. PloS Negl Trop Dis, 2008; 2(4): e215.
[18] Ketloy C, Engering A, Srichairatanakul U, et al. Expression and function of toll-like receptors on dendritic cells and other antigen presenting cells from non-human primates. Vet Immunol Immunopathol, 2008; 125(1-2): 18-30.
[19] Edwards AD, Diebold SS, Slack EM, et al. Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α+ DC correlates with unresponsiveness to imidazoquinolines. Eur J Immunol, 2003; 33(4): 827-833.
[20] Maldonado-Lopez R, De Smedt T, Pajak B, et al. Role of CD8α+ and CD8α? dendritic cells in the induction of primary immune responses in vivo. J Leukoc Biol, 1999; 66(2): 242-246.
[21] Manickasingham SP, Edwards AD, Schulz O, et al. The ability of murine dendritic cell subsets to direct Th differentiation is dependent on microbial signals. Eur J Immunol, 2003; 33(1): 101-107.
[22] Blander JM. Coupling Toll-like receptor signaling with phagocytosis: potentiation of antigen presentation. Trends Immunol, 2007; 28(1): 19-25.
[23] Blander J M, Medzhitov R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature, 2006; 440(7085): 808-812.
[24] Delamarre L, Holcombe H, Meilman I. Presentation of exogenous antigens on Major Histocompatibility Complex (MHC) class I and MHC class II molecules isdifferentially regulated during dendritic cell maturation. J Exp Med, 2003; 198(1): 111-122.
[25] Datta SK, Redecke V, Prilliman KR, et al. A subset of toll-like receptor ligands induces cross-presentation by bone marrow-derived dendritic cells. J Immunol, 2003; 170(8): 4102-4110.
[26] Boele LC, Bajramovic JJ, de-Vries AM, et al. Activation of toll-like receptors and dendritic cells by a broad range of bacterial molecules. Cell Immunol, 2009; 255(1-2): 17-25.
[27] Hoshino K, Kaisho T, Iwabe T, et al. Differential involvement of IFN-beta in toll-like receptor-stimulated dendritic cell activation. Int Immunol, 2002; 14(10): 1225-1231.
[28] Mattei F, Schiavoni G, Belardelli F, et al. IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J Immunol, 2001; 167(3): 1179-1187.
[29] Lebre MC, Antons JC, Kalinski P, et al. Double-stranded RNA-exposed human keratinocytes promote Th1 responses by inducing a type-1 polarized phenotype in dendritic cells: role of keratinocyte-derived tumor necrosis factor alpha, type I interferons, and interleukin-18. J Invest Dermatol, 2003; 120(6): 990-997.
[30] Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science, 2003; 299(5609): 1033-1036.
[31] Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol, 2002; 20: 709-760.
[32] Boullart AC, Aarntzen EH, Verdijk P, et al. Maturation of monocyte-derived dendritic cells with toll-like receptor 3 and 7/8 ligands combined with prostaglandin E2 results in high interleukin-12 production and cell migration. Cancer Immunol Immunother, 2008; 57(11): 1589-1597.
[33] Cao W, Liu YJ. Innate immune functions of plasmacytoid dendritic cells. Curr Opin Immunol, 2007; 19:(1) 24-30.
[34] Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell, 2008; 132(3): 344-362.
[35] Kawai T, Akira S. Signaling to NF-kappaB by toll-like receptors. Trends Mol Med, 2007; 13(11): 460-469.
[36] Kaisho T, Takeuchi O, Kawai T, et al. Endotoxin-induced maturation ofMyD88-deficient dendritic cells. J Immunol, 2001; 166(9): 5688-5694.
[37] Yamamoto M, Sato S, Hemmi H, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science, 2003; 301(5633): 640-643.
[38] Beutler B. Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases. Immunol Rev, 2009; 227(1): 248-263.
[39] Beutler BA. TLRs and innate immunity. Blood, 2009; 113(7): 1399-1407.
[40] Foster SL, Medzhitov R. Gene-specific control of the TLR-inducedinflammatory response. Clin Immunol, 2009; 130(1): 7-15.
[41] Fukao T, TanabeM, Terauchi Y, et al. PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nat Immunol, 2002; 3(9): 875-881.
[42] Dalpke A, Heeg K, Bartz H, et al. Regulation of innate immunity by suppressor of cytokine signaling (SOCS) proteins. Immunobiology, 2008; 213(304): 225-235.
[43] Mansell A, Smith R, Doyle SL, et al. Suppressor of cytokine signaling 1 negatively regulates toll-like receptor signaling by mediating Mal degradation. Nat Immunol, 2006; 7(2):148-155.
[44] Manicassamy S, Ravindran R, Deng J, et al. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat Med, 2009; 15(4): 401-409.
[45] Mbow ML, Sarisky M. Modulating toll-like receptor signalling as a novel antiinfective approach. Drug News Perspect, 2005; 18(3): 179-184.