TLRs激动剂对红外期疟原虫发育的影响与机制研究
发布时间：2019-06-09 13:53
【摘要】： 疟疾是蚊媒传播的严重危害人类健康的热带传染病,在全世界人群中具有很高的发病率和致死率。按蚊叮刺时将疟原虫子孢子注入宿主体内,随后子孢子进入血液循环,并可在数分钟后迅速侵入肝细胞。经短暂的红外期增殖发育,裂殖子再次进入血液循环、侵入红细胞导致疟疾临床发作。疟原虫在红外期的增殖发育是疟疾生活史中的重要阶段,而阻断虫体在肝脏内的增殖发育,即可防止疟原虫红内期感染。另外,红外期休眠子的存在是导致间日疟原虫临床病例复发的重要原因。因此,红外期是制定干预疟原虫感染措施的理想时期,阻断红外期疟原虫生长发育能从源头控制疟原虫的感染。然而,目前尚无有效的红外期疫苗和预防药物,迫切需要新的疟疾防治手段和策略。 子孢子经按蚊叮咬注入宿主后,必须且只有侵入肝细胞并在肝细胞内进行发育。鼠疟在肝细胞内43h后发育成熟,随后肝细胞逐渐破裂并释放出裂殖子。同样,人疟的红外期周期约为1周~10多天,裂殖子进入血液循环后发育成红内期疟原虫,将不会再返回肝脏。红内期疟原虫能够反复感染红细胞,宿主能够产生适应性免疫。然而,红外期是疟原虫侵入宿主的早期,周期短暂,宿主不能及时产生适应性免疫,主要依赖天然免疫抑制子孢子入侵肝细胞。在子孢子侵入过程中,大量的天然免疫细胞,如DCs、NK、NKT、γδT等细胞被激活,通过细胞毒效应或分泌细胞因子IL-12、IFN-γ、TNF-α等抑制疟原虫子孢子感染肝细胞,并能够影响CD4+和CD8+ T细胞对红外期疟原虫的免疫应答类型。因此,天然免疫对抑制红外期疟原虫发育十分重要,探讨宿主天然免疫抗红外期疟原虫机制是制定新的疟疾防治措施的前提。 TLRs(Toll-like receptors)受体是天然免疫细胞的重要模式识别分子,其介导的信号是天然免疫的重要组成部分。不同的TLRs能识别不同的病原体成分,如TLR2识别脂蛋白(Lipoprotein)、磷壁酸(Lipoteinchoic acid, LTA)和酵母聚糖(Zymosan),TLR3识别病毒dsRNA,TLR4识别脂多糖(LPS),TLR5识别鞭毛蛋白(Flagellin),TLR7/8识别小分子化合物如咪喹莫特(Imiquimod)和单链RNA,而TLR9特异性识别细菌DNA中的非甲基化CpG-ODN序列。TLRs表达于多种天然免疫细胞,如巨噬细胞,DC细胞,B细胞等。这些天然免疫细胞能在感染早期通过TLRs受体识别入侵的病原体而被活化,进而激活NF-κB和转录因子AP-1,促进IL-12、TNF-α、IL-1β和IL-6等炎症因子的大量分泌,从而抑制病原体的增殖和扩散。研究证实,TLRs信号通路提前活化后能有效地抑制弓形虫、细菌和病毒的感染。然而,目前还没有资料显示提前活化TLRs信号通路能否影响且有效抑制红外期疟原虫的增殖与发育。 本研究通过约氏疟原虫-BABL/c小鼠模型,以肝脏虫荷和原虫血症为检测指标,对不同TLRs激动剂在红外期疟原虫增殖发育中的作用进行研究。其实验内容和结果主要包括以下四个方面: 一、构建约氏疟原虫BY265株18S rRNA重组质粒:通过对多种疟原虫18S rRNA基因的生物信息学分析,根据保守序列设计P.y. BY265株18S rRNA的特异性引物并进行分子克隆。重组质粒测序结果显示该片段长度为839bp,经Blast分析发现它与约氏疟原虫17XNL株相似性为98%。 二、构建Real-time PCR红外期疟原虫检测平台:在P.y. BY265株18S rRNA重组质粒的基础上,设计Real-time PCR特异性的引物和TaqMan探针,并与小鼠GAPDH特异性的Real-time PCR引物和TaqMan探针共同组成红外期疟原虫Real-time PCR检测平台。以约氏疟原虫-BABL/c小鼠模型,通过对50、100、500和1000个唾液腺子孢子感染小鼠的肝脏虫荷进行定量分析,结果显示Real-time PCR检测平台能够检测到最低为50个子孢子剂量感染的小鼠肝脏虫荷。 三、以Real-time PCR为基础,系统的对不同TLRs激动剂在红外期疟原虫增殖发育中的作用和影响进行了研究:在单个TLRs激动剂尾静脉注入小鼠24h后,将100个成熟的唾液腺子孢子再注入小鼠,部分小鼠在疟原虫感染后42h取出肝脏进行Real-time PCR分析,部分小鼠在疟原虫感染后4~14天内进行原虫血症检查。结果显示,在该剂量下部分TLRs激动剂能够显著抑制红外期疟原虫的发育,而部分TLRs激动剂对红外期疟原虫的发育无显著影响,反而对红内期的疟原虫发育具有一定的促进作用: 1.在等量TLRs激动剂的作用下,TLR2、TLR3、TLR4和TLR9激动剂能够显著减少小鼠的肝脏虫荷,其中以TLR9激动剂的作用最强,不仅能够将100个唾液腺子孢子感染小鼠的肝脏虫荷减少约90%,而且还能推迟红内期原虫血症的出现。当增加疟原虫子孢子感染剂量后,肝脏虫荷和原虫血症均有一定的增高,但与对照组相比,TLR9激动剂均能显著减少肝脏虫荷及延迟原虫血症发生。因此,活化TLR9信号通路诱导的免疫应答在抑制红外期疟原虫增殖发育中具有重要的作用。 2.与其它激动剂相同剂量的TLR5和TLR7激动剂对疟原虫感染小鼠的肝脏虫荷变化无显著影响。然而,原虫血症结果显示,TLR5激动剂处理组小鼠的红内期原虫血症在感染8天后高于对照组,提示激活TLR5信号通路可能有利于红内期疟原虫的增殖发育。 四、探讨TLR9激动剂和TLR5激动剂影响疟原虫发育的免疫机制: 1.TLR9激动剂与枯否细胞:枯否细胞(Kupffer cells,KC)是疟原虫子孢子侵入肝细胞的重要门户。在氯化钆(GdCl3)特异性阻断KC的吞噬功能后,TLR9激动剂抑制红外期疟原虫发育的功能显著下降,提示TLR9激动剂通过增强KC细胞吞噬功能抑制红外期疟原虫的发育;然而,GdCl3无法完全消除TLR9激动剂的抑制作用,提示TLR 9激动剂还能激活其它的抗疟原虫免疫机制。 2.TLR9激动剂与肝脏细胞因子:细胞因子是重要的抗疟原虫效应分子。本课题在进一步研究中发现,TLR9激动剂能够上调肝脏内促炎症因子IFN-γ、IL-12、TNF-α基因的mRNA表达,而下调抗炎症因子IL-10和TGF-β基因的mRNA表达,提示TLR9激动剂能够诱导产生肝脏细胞因子抑制红外期疟原虫的发育。 3.TLR5激动剂与红内期疟原虫:将TLR5重组真核表达质粒转染HEK293细胞,经疟原虫感染的红细胞及其裂解物分别刺激后,双荧光素酶实验结果显示实验组的荧光相对比值显著增高,且完整的感染红细胞刺激组显著高于其裂解物刺激组,提示疟原虫感染的红细胞能够激活TLR5信号通路及感染的红细胞膜上可能存在TLR5的配体。根据文献推测,该配体可能通过活化TLR5信号通路激活调节性T细胞(Treg)从而降低机体对病原体的免疫应答。 本课题通过建立有效的红外期疟原虫定量检测平台,系统观察提前24h激活TLRs信号通路对红外期疟原虫发育的影响。TLR2、TLR3、TLR4和TLR9激动剂能够显著抑制红外期疟原虫的发育,其中TLR9激动剂抑制作用最强,能够显著抑制疟原虫感染小鼠的肝脏虫荷并推迟原虫血症的出现。深入研究发现TLR9激动剂通过增强KC细胞吞噬功能和诱导产生肝脏细胞因子等免疫效应抑制红外期疟原虫的发育;然而,相同剂量的TLR5和TLR7激动剂,对红外期疟原虫的发育无显著影响。但有意思的是,TLR5激动剂处理小鼠的原虫血症高于对照组,且在双荧光素酶实验中发现红内期疟原虫能够激活TLR5信号通路,提示红内期疟原虫可能存在TLR5激动剂。这些结果对于我们认识抗疟原虫红外期天然免疫机制和深入探索宿主的天然免疫识别及疟原虫的免疫逃避的关系,并可为疟疾免疫防治提供理论依据。
[Abstract]:Malaria is a tropical infectious disease that is a serious threat to human health by mosquito-borne diseases, and has a high morbidity and mortality in the worldwide population. The sporozoites of the plasmodium are injected into the host body when the mosquito is stabbed, and then the sporozoites enter the blood circulation and can rapidly enter the liver cells after a few minutes. After a brief infrared period of proliferation and development, the merozoites enter the blood circulation again, and the invading red blood cells cause the clinical attack of the malaria. The proliferation and development of plasmodium in the infrared period is an important stage in the life history of malaria, and the proliferation and development of the insect body in the liver can be blocked, and the infection of the plasmodium in the red inner phase can be prevented. In addition, the existence of the dormancy of the infrared period is an important cause of the recurrence of the clinical cases of Plasmodium vivax. Therefore, the infrared period is an ideal period for the development of the infection of Plasmodium vivax, which can block the infection of the plasmodium from the source by blocking the growth and development of the plasmodium. However, there are currently no effective infrared vaccines and preventive drugs, and there is an urgent need for new methods and strategies for malaria control. After the sporozoites are injected into the host according to the bite of the mosquito, it is necessary and only to invade the liver cells and enter the liver cells. The mouse malaria developed in the liver for 43 h, and then the liver cells were gradually broken and released. In the same way, the period of the infrared period of the human malaria is about 1 week to 10 days, and after the merozoites enter the blood circulation, the plasmodium is developed into the red-period plasmodium, and will not be returned again. Back to the liver. Plasmodium vivax can repeatedly infect the red blood cells, and the host can produce the adaptation. However, the infrared period is the early stage of the invasion of the parasite into the host, the period is short, the host can not produce the adaptive immunity in time, mainly relying on the natural immunosuppression subspore invasion In the process of subspore invasion, a large amount of natural immune cells, such as DCs, NK, NKT, and T-like cells, are activated to inhibit the infection of the sporozoites of the plasmodium by the cytotoxic effect or the secretion of the cytokine IL-12, IFN-1, TNF-1, and the like. The immune response of the CD4 + and CD8 + T cells to the plasmodium of the infrared period can be influenced by the liver cells. Therefore, the natural immunity is very important to the inhibition of the development of plasmodium in the infrared period, and the mechanism of the host natural immune anti-infrared period is to develop new malaria control measures The TLRs (Toll-like receptors) receptor is an important pattern recognition molecule of natural immune cells. The different TLRs can identify different pathogen components, such as TLR2, Lipoprotein, LTA and Zymosan, TLR3 recognizes the viral dsRNA, TLR4 recognizes lipopolysaccharide (LPS), TLR5 recognizes flagellin (Fla). gellin), TLR7/8 recognizes a small molecule compound such as Imiquimod and single-stranded RNA, while TLR9 specifically recognizes the non-methylated Cp in the bacterial DNA G-ODN sequence. TLRs are expressed in a variety of natural immune cells, such as macrophages, DCs, The natural immune cells can be activated by identifying the invading pathogens in the early stage of infection by the TLRs receptor, so as to activate the NF-B and the transcription factor AP-1 to promote a large amount of secretion of the inflammatory factors such as IL-12, TNF-1, IL-1, and IL-6, thereby inhibiting the pathogen. It is proved that the TLRs can effectively inhibit Toxoplasma gondii and fine after the early activation of the signal pathway of the TLRs. However, there is no information on whether the early activation of the TLRs signal pathway can affect and effectively inhibit the infrared malarial. The effects of different TLRs on the proliferation and development of the worm were studied by using the model of Plasmodium yoelii-BABL/ c. A study of the role of the development of colonisation. The results mainly include the following four aspects:1. Construction of the 18S rRNA recombinant plasmid of the BY265 strain of the Plasmodium yoelii. The 18S rR of the P. y. BY265 strain 18S rR is designed according to the conserved sequence by the bioinformatics analysis of the 18S rRNA gene of the plasmodium. The specific primers of NA and the molecular cloning were carried out. The results of the recombinant plasmid sequencing showed that the length of the fragment was 839 bp, and it was found to be in the form of some malaria by the Blast analysis. A real-time PCR-specific primer and a TaqMan probe were designed on the basis of the 18S rRNA recombinant plasmid of P. y. BY265, and the real-time PCR primer and the TaqMan probe specific to the mouse GAPDH were combined to form the infrared phase. Plasmodium vivax-BABL/ c mouse model, a quantitative analysis of the liver worm of mice infected with 50,100,500 and 1000 salivary glands was carried out, and the results showed that the real-time PCR detection platform was able to detect the most The effects and effects of different TLRs agonists on the proliferation and development of Plasmodium vivax were studied on the basis of Real-time PCR. After 4 h,100 mature salivary gland subspores were re-injected into the mice, and some of the mice were taken out of the liver for real-time PCR analysis at 42 h after the infection of the plasmodium. The results show that the partial TLRs agonist can significantly inhibit the development of the plasmodium in the infrared period, while the partial TLRs agonist has no significant effect on the development of the plasmodium in the infrared period. In response, the effects of TLR2, TLR3, TLR4 and TLR9 agonist on the development of the plasmodium in the red inner stage can significantly reduce the liver insect-loading of the mice, and the effect of the TLR9 agonist is the strongest, not only can the TLR2, TLR3, TLR4 and TLR9 agonists Enough to infect the 100 salivary gland subspores to the mice. The decrease of the liver worm was reduced by about 90%, and the occurrence of the endotoxemia in the red endothelia could be delayed. After the infection of the sporozoites of the plasmodium, the liver and the protozoan were increased, but compared with the control group. The TLR9 agonist can significantly reduce the occurrence of hepatic and delayed protozoan. Therefore, the activation of TLR9 signaling pathway the immune response of the derivative plays an important role in the inhibition of the proliferation and development of the Plasmodium vivax.2. The same dose of T as other agonists The LR5 and TLR7 agonists have no significant effect on the changes in the liver of the mice infected with plasmodium. However, the results of the protozoa show that the red endotoxemia of the TLR5 agonist treatment group mice is higher than in the case of 8 days of infection In group, it is suggested that the activation of TLR5 signal pathway may be beneficial to the proliferation and development of Plasmodium vivax. 4. To study the immune mechanism of TLR9 agonists and TLR5 agonists to the development of plasmodium:1. TLR9 agonists and dead cells : Kupffer cells (KC) is an important portal for the invasion of the sporozoites of the plasmodium. After the specific blocking of the phagocytosis of the KC, the TLR9 agonist inhibits the development of the Plasmodium vivax. It is suggested that the TLR9 agonist can inhibit the development of the infrared stage plasmodium by enhancing the phagocytosis of the KC cells; however, the GdCl3 can not be completely The inhibition of TLR9 agonists is eliminated, suggesting that the TLR 9 agonist can also activate other antimalarial precursors in a further study, TLR9 agonists are able to upregulate that inflammatory factor IFN-1, IL-12 in the liver, The mRNA expression of the TNF-1 gene and the down-regulation of the anti-inflammatory factors IL-10 and TGF- 3. TLR5 agonists and plasmodium vivax: the recombinant eukaryotic expression plasmid of TLR5 was transfected into HEK293 cells. After stimulation of the red blood cells and the lysates of the plasmodium, the results of the two-luciferase experiment show that the relative ratio of the fluorescence in the experimental group is significantly higher, and the complete infection of the red blood cell stimulation group is significantly higher than the lysate thereof. In the stimulation group, the red blood cells infected with the plasmodium can activate the TLR5 signaling pathway and the potential TLR5 ligand on the infected red cell membrane. The ligand may activate regulatory T cells (Treg) by activating the TLR5 signaling pathway to reduce the immune response of the body to the pathogen. The effects of the activation of TLRs on the development of Plasmodium vivax were observed by establishing an effective quantitative detection platform for Plasmodium vivax. TLR2, TLR3, TLR4 and TLR9 agonists can significantly inhibit the infrared period. The development of the plasmodium, in which the inhibitory effect of the TLR9 agonist is the strongest, can significantly inhibit the liver of the mice infected with the plasmodium, and delay the occurrence of the protozoan. In-depth study of the discovery of TLR9 agonists by enhancing the phagocytosis of the KC and the induction of the production of the liver cytokines, etc. The effects of phytophthora blight on the development of plasmodium in the infrared period were inhibited; however, the same dose of TLR5 and TLR7 agonists had no significant effect on the development of Plasmodium vivax, but it was interesting that the TLR5 agonist treated mice with a higher protozoan effect than that of the control group. In that double-luciferase experiment, the TLR5 signal pathway can be activated by the plasmodium vivax, suggesting that a TLR5 agonist may be present in the red endoplasmodium.
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R392
本文编号：2495602
[Abstract]:Malaria is a tropical infectious disease that is a serious threat to human health by mosquito-borne diseases, and has a high morbidity and mortality in the worldwide population. The sporozoites of the plasmodium are injected into the host body when the mosquito is stabbed, and then the sporozoites enter the blood circulation and can rapidly enter the liver cells after a few minutes. After a brief infrared period of proliferation and development, the merozoites enter the blood circulation again, and the invading red blood cells cause the clinical attack of the malaria. The proliferation and development of plasmodium in the infrared period is an important stage in the life history of malaria, and the proliferation and development of the insect body in the liver can be blocked, and the infection of the plasmodium in the red inner phase can be prevented. In addition, the existence of the dormancy of the infrared period is an important cause of the recurrence of the clinical cases of Plasmodium vivax. Therefore, the infrared period is an ideal period for the development of the infection of Plasmodium vivax, which can block the infection of the plasmodium from the source by blocking the growth and development of the plasmodium. However, there are currently no effective infrared vaccines and preventive drugs, and there is an urgent need for new methods and strategies for malaria control. After the sporozoites are injected into the host according to the bite of the mosquito, it is necessary and only to invade the liver cells and enter the liver cells. The mouse malaria developed in the liver for 43 h, and then the liver cells were gradually broken and released. In the same way, the period of the infrared period of the human malaria is about 1 week to 10 days, and after the merozoites enter the blood circulation, the plasmodium is developed into the red-period plasmodium, and will not be returned again. Back to the liver. Plasmodium vivax can repeatedly infect the red blood cells, and the host can produce the adaptation. However, the infrared period is the early stage of the invasion of the parasite into the host, the period is short, the host can not produce the adaptive immunity in time, mainly relying on the natural immunosuppression subspore invasion In the process of subspore invasion, a large amount of natural immune cells, such as DCs, NK, NKT, and T-like cells, are activated to inhibit the infection of the sporozoites of the plasmodium by the cytotoxic effect or the secretion of the cytokine IL-12, IFN-1, TNF-1, and the like. The immune response of the CD4 + and CD8 + T cells to the plasmodium of the infrared period can be influenced by the liver cells. Therefore, the natural immunity is very important to the inhibition of the development of plasmodium in the infrared period, and the mechanism of the host natural immune anti-infrared period is to develop new malaria control measures The TLRs (Toll-like receptors) receptor is an important pattern recognition molecule of natural immune cells. The different TLRs can identify different pathogen components, such as TLR2, Lipoprotein, LTA and Zymosan, TLR3 recognizes the viral dsRNA, TLR4 recognizes lipopolysaccharide (LPS), TLR5 recognizes flagellin (Fla). gellin), TLR7/8 recognizes a small molecule compound such as Imiquimod and single-stranded RNA, while TLR9 specifically recognizes the non-methylated Cp in the bacterial DNA G-ODN sequence. TLRs are expressed in a variety of natural immune cells, such as macrophages, DCs, The natural immune cells can be activated by identifying the invading pathogens in the early stage of infection by the TLRs receptor, so as to activate the NF-B and the transcription factor AP-1 to promote a large amount of secretion of the inflammatory factors such as IL-12, TNF-1, IL-1, and IL-6, thereby inhibiting the pathogen. It is proved that the TLRs can effectively inhibit Toxoplasma gondii and fine after the early activation of the signal pathway of the TLRs. However, there is no information on whether the early activation of the TLRs signal pathway can affect and effectively inhibit the infrared malarial. The effects of different TLRs on the proliferation and development of the worm were studied by using the model of Plasmodium yoelii-BABL/ c. A study of the role of the development of colonisation. The results mainly include the following four aspects:1. Construction of the 18S rRNA recombinant plasmid of the BY265 strain of the Plasmodium yoelii. The 18S rR of the P. y. BY265 strain 18S rR is designed according to the conserved sequence by the bioinformatics analysis of the 18S rRNA gene of the plasmodium. The specific primers of NA and the molecular cloning were carried out. The results of the recombinant plasmid sequencing showed that the length of the fragment was 839 bp, and it was found to be in the form of some malaria by the Blast analysis. A real-time PCR-specific primer and a TaqMan probe were designed on the basis of the 18S rRNA recombinant plasmid of P. y. BY265, and the real-time PCR primer and the TaqMan probe specific to the mouse GAPDH were combined to form the infrared phase. Plasmodium vivax-BABL/ c mouse model, a quantitative analysis of the liver worm of mice infected with 50,100,500 and 1000 salivary glands was carried out, and the results showed that the real-time PCR detection platform was able to detect the most The effects and effects of different TLRs agonists on the proliferation and development of Plasmodium vivax were studied on the basis of Real-time PCR. After 4 h,100 mature salivary gland subspores were re-injected into the mice, and some of the mice were taken out of the liver for real-time PCR analysis at 42 h after the infection of the plasmodium. The results show that the partial TLRs agonist can significantly inhibit the development of the plasmodium in the infrared period, while the partial TLRs agonist has no significant effect on the development of the plasmodium in the infrared period. In response, the effects of TLR2, TLR3, TLR4 and TLR9 agonist on the development of the plasmodium in the red inner stage can significantly reduce the liver insect-loading of the mice, and the effect of the TLR9 agonist is the strongest, not only can the TLR2, TLR3, TLR4 and TLR9 agonists Enough to infect the 100 salivary gland subspores to the mice. The decrease of the liver worm was reduced by about 90%, and the occurrence of the endotoxemia in the red endothelia could be delayed. After the infection of the sporozoites of the plasmodium, the liver and the protozoan were increased, but compared with the control group. The TLR9 agonist can significantly reduce the occurrence of hepatic and delayed protozoan. Therefore, the activation of TLR9 signaling pathway the immune response of the derivative plays an important role in the inhibition of the proliferation and development of the Plasmodium vivax.2. The same dose of T as other agonists The LR5 and TLR7 agonists have no significant effect on the changes in the liver of the mice infected with plasmodium. However, the results of the protozoa show that the red endotoxemia of the TLR5 agonist treatment group mice is higher than in the case of 8 days of infection In group, it is suggested that the activation of TLR5 signal pathway may be beneficial to the proliferation and development of Plasmodium vivax. 4. To study the immune mechanism of TLR9 agonists and TLR5 agonists to the development of plasmodium:1. TLR9 agonists and dead cells : Kupffer cells (KC) is an important portal for the invasion of the sporozoites of the plasmodium. After the specific blocking of the phagocytosis of the KC, the TLR9 agonist inhibits the development of the Plasmodium vivax. It is suggested that the TLR9 agonist can inhibit the development of the infrared stage plasmodium by enhancing the phagocytosis of the KC cells; however, the GdCl3 can not be completely The inhibition of TLR9 agonists is eliminated, suggesting that the TLR 9 agonist can also activate other antimalarial precursors in a further study, TLR9 agonists are able to upregulate that inflammatory factor IFN-1, IL-12 in the liver, The mRNA expression of the TNF-1 gene and the down-regulation of the anti-inflammatory factors IL-10 and TGF- 3. TLR5 agonists and plasmodium vivax: the recombinant eukaryotic expression plasmid of TLR5 was transfected into HEK293 cells. After stimulation of the red blood cells and the lysates of the plasmodium, the results of the two-luciferase experiment show that the relative ratio of the fluorescence in the experimental group is significantly higher, and the complete infection of the red blood cell stimulation group is significantly higher than the lysate thereof. In the stimulation group, the red blood cells infected with the plasmodium can activate the TLR5 signaling pathway and the potential TLR5 ligand on the infected red cell membrane. The ligand may activate regulatory T cells (Treg) by activating the TLR5 signaling pathway to reduce the immune response of the body to the pathogen. The effects of the activation of TLRs on the development of Plasmodium vivax were observed by establishing an effective quantitative detection platform for Plasmodium vivax. TLR2, TLR3, TLR4 and TLR9 agonists can significantly inhibit the infrared period. The development of the plasmodium, in which the inhibitory effect of the TLR9 agonist is the strongest, can significantly inhibit the liver of the mice infected with the plasmodium, and delay the occurrence of the protozoan. In-depth study of the discovery of TLR9 agonists by enhancing the phagocytosis of the KC and the induction of the production of the liver cytokines, etc. The effects of phytophthora blight on the development of plasmodium in the infrared period were inhibited; however, the same dose of TLR5 and TLR7 agonists had no significant effect on the development of Plasmodium vivax, but it was interesting that the TLR5 agonist treated mice with a higher protozoan effect than that of the control group. In that double-luciferase experiment, the TLR5 signal pathway can be activated by the plasmodium vivax, suggesting that a TLR5 agonist may be present in the red endoplasmodium.
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R392
【共引文献】
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10 Guiyun Cui;Xiaopeng Wang;Xinchun Ye;Jie Zu;Kun Zan;Fang Hua;;Oxygen-glucose deprivation of neurons transfected with toll-like receptor 3-siRNA Determination of an optimal transfection sequence[J];Neural Regeneration Research;2013年34期
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